U.S. patent number 10,072,014 [Application Number 15/533,308] was granted by the patent office on 2018-09-11 for 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglur2 receptors.
This patent grant is currently assigned to JANSSEN PHARMACEUTICA NV. The grantee listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Manuel Jes s Alcazar-Vaca, Sergio-Alvar Alonso-de Diego, Ana Isabel De Lucas Olivares, Michiel Luc Maria Van Gool.
United States Patent |
10,072,014 |
Van Gool , et al. |
September 11, 2018 |
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one compounds and their use
as negative allosteric modulators of MGLUR2 receptors
Abstract
The present invention relates to novel
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negative
allosteric modulators (NAMs) of the metabotropic glutamate receptor
subtype 2 ("mGluR2"). The invention is also directed to
pharmaceutical compositions comprising such compounds, to processes
for preparing such compounds and compositions, and to the use of
such compounds and compositions for the prevention or treatment of
disorders in which the mGluR2 subtype of metabotropic receptors is
involved.
Inventors: |
Van Gool; Michiel Luc Maria
(Madrid, ES), Alcazar-Vaca; Manuel Jes s (Toledo,
ES), Alonso-de Diego; Sergio-Alvar (Toledo,
ES), De Lucas Olivares; Ana Isabel (Toledo,
ES) |
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
N/A |
BE |
|
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Assignee: |
JANSSEN PHARMACEUTICA NV
(Beerse, BE)
|
Family
ID: |
52002818 |
Appl.
No.: |
15/533,308 |
Filed: |
December 2, 2015 |
PCT
Filed: |
December 02, 2015 |
PCT No.: |
PCT/EP2015/078285 |
371(c)(1),(2),(4) Date: |
June 05, 2017 |
PCT
Pub. No.: |
WO2016/087487 |
PCT
Pub. Date: |
June 09, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170369493 A1 |
Dec 28, 2017 |
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Foreign Application Priority Data
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Dec 3, 2014 [EP] |
|
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14196082 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
25/32 (20180101); A61P 25/34 (20180101); C07D
487/04 (20130101); A61K 31/4985 (20130101); A61P
25/18 (20180101); A61P 25/24 (20180101); A61P
25/00 (20180101); A61P 25/26 (20180101); A61P
25/30 (20180101); A61P 25/14 (20180101); A61P
25/36 (20180101); A61P 43/00 (20180101); A61P
25/28 (20180101) |
Current International
Class: |
C07D
487/04 (20060101); A61K 31/4985 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0756200 |
|
Jan 1997 |
|
EP |
|
2327704 |
|
Jun 2011 |
|
EP |
|
2002096873 |
|
Dec 2002 |
|
WO |
|
2005002552 |
|
Jan 2005 |
|
WO |
|
2005061507 |
|
Jul 2005 |
|
WO |
|
2006030847 |
|
Mar 2006 |
|
WO |
|
2006050803 |
|
May 2006 |
|
WO |
|
2007084314 |
|
Jul 2007 |
|
WO |
|
2008001115 |
|
Jan 2008 |
|
WO |
|
2008141239 |
|
Nov 2008 |
|
WO |
|
2009095872 |
|
Aug 2009 |
|
WO |
|
2009118292 |
|
Oct 2009 |
|
WO |
|
2009130232 |
|
Oct 2009 |
|
WO |
|
2010130423 |
|
Nov 2010 |
|
WO |
|
2010130424 |
|
Nov 2010 |
|
WO |
|
2012035078 |
|
Mar 2012 |
|
WO |
|
2012062752 |
|
May 2012 |
|
WO |
|
2012083224 |
|
Jun 2012 |
|
WO |
|
2012143726 |
|
Oct 2012 |
|
WO |
|
2013012915 |
|
Jan 2013 |
|
WO |
|
2013012918 |
|
Jan 2013 |
|
WO |
|
2013066736 |
|
May 2013 |
|
WO |
|
2013154878 |
|
Oct 2013 |
|
WO |
|
2013156869 |
|
Oct 2013 |
|
WO |
|
2013174822 |
|
Nov 2013 |
|
WO |
|
2014064028 |
|
May 2014 |
|
WO |
|
2014195311 |
|
Dec 2014 |
|
WO |
|
016380 |
|
Feb 2016 |
|
WO |
|
016395 |
|
Feb 2016 |
|
WO |
|
2016016362 |
|
Feb 2016 |
|
WO |
|
2016016381 |
|
Feb 2016 |
|
WO |
|
2016016383 |
|
Feb 2016 |
|
WO |
|
2016087487 |
|
Jun 2016 |
|
WO |
|
2016087489 |
|
Jun 2016 |
|
WO |
|
2017103179 |
|
Jun 2017 |
|
WO |
|
2017103182 |
|
Jun 2017 |
|
WO |
|
Other References
Dinklo Theo et al, Characterization of
2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyi)-5-
thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric
Modulator of the 7 Nicotinic Acetylcholine Receptor S, The Journal
of Pharmacology and Experimental Therapeutics, 2011, pp. 560-574,
vol. 336 No. 2. cited by applicant .
Guy A. Higgins et al., Pharmacological manipulation of mGlu2
receptors influences, Neuropharmacology, 2004, pp. 907-917, vol.
46. cited by applicant .
Hickinbottom, English translation of the relevent from reaction of
organic complonents, Reactions of organic compounds, 1939, pp.
360-362, Page Number. cited by applicant .
Lynne Gilfillian et al, Synthesis and biological evaluation of
novel 2,3-dihydro-1H-1,5-benzodiazepin-2-ones; potential imaging
agents of the metabotropic glutamate 2 receptor, Med. Chem.
Commun,, May 29, 2013, pp. 1118-1123, vol. 4 Issue 7. cited by
applicant .
Serena Bigotti et al, Synthesis of C[CH(RF)NH]Gly-peptides: The
dramatic effect of a single fluorine atom on the diastereocontrol
of the key aza-Michael reaction, Journal of Fluorine Chemistry,
Jun. 27, 2008, pp. 767-774, 129. cited by applicant .
Shigemoto, et al, Differential Presynaptic Localization of
Metabotropic Glutamate Receptor Subtypes in the Rat Hippocarnpus,
The Journal of Neuroscience, Oct. 1, 1997, pp. 7503-7522, vol. 17
Issue 19, Society for Neuroscience. cited by applicant .
Vippagunta et al, Crystalline solids, Advanced Drug Delivery
Reviews, May 16, 2001, pp. 3-26, vol. 48 No. 1. cited by applicant
.
Moskva, et al., English translation of the relvant parts from
"Khimicheskaya enclopedia", v. 1 izadatelstvo "Sovestskay
encyclopedia", Moskva, 1988, pp. 242-243. cited by applicant .
International Search Report re: PCT/EP2015/078285 dated Feb. 1,
2016. cited by applicant .
International Search Report re: PCT/EP2015/078296 dated Feb. 19,
2016. cited by applicant .
International Search Report re: PCT/EP2015/079216 dated Feb. 25,
2016. cited by applicant .
Alfonso R Gennaro, 18th edition Remington's--Pharmaceutical
Sciences, 18th edition Remington's--Pharmaceutical Sciences, 1990,
Part 8_ Pharmaceutical preparations and their Manufacture_ pp.
1435-1714, Part 8. cited by applicant .
Alper R. et al, Agonist-Stimulated [35S]GTBgS Binding, Current
Protocols in Pharmacology, 1998, suppl.2, -. cited by applicant
.
Anonymous, A study to assess the relative bioavailability of TMC207
Following single-dose administrations of two pediatric formulations
in healthy adult participants, /, Mar. 2014, /, /. cited by
applicant .
Celia Goeldner, Cognitive impairment in major depression and the
mG1u2 receptor as a therapeutic target, Neuropharmacology, Aug. 3,
2013, pp. 337-346, 64. cited by applicant .
Cid Jose Maria et al, Discovery of
3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]tr-
iazolo [4,3-a]pyridine (JNJ-42153605): A Positive Allosteric
Modulator of the Metabotropic Glutamate 2 Receptor, Journal of
Medicinal Chemistry, Oct. 16, 2012, pp. 8770-8789, 55. cited by
applicant .
D. S. Ermolat'ev et al, One-pot microwave-assisted protocol for the
synthesis, Mol Divers, Aug. 26, 2010, pp. vol. 15 491-496, vol. 15.
cited by applicant .
Ferraguti,et al, Metabotropic glutamate receptors, Cell &
Tissue Research, Jul. 18, 2006, pp. 483-504, 326. cited by
applicant .
Hiroyuki Koike et al, Role of BDNF/TrkB signaling in
antidepressant-like effects of a group II metabotropic glutamate
receptor antagonist in animal models of depression, Behavioural
Brain Research, Oct. 23, 2012, pp. 48-52, 238. cited by applicant
.
Kelmendi et al, The role of the Glutamatergic system in the
pathophysiology and treatment of mood disorders, Primary
Psychiatry, Oct. 2006, pp. 80-86, vol. 13 No. 10. cited by
applicant .
Niswender Colleen M. et al, Metabotropic Glutamate Receptors:
Physiology, Pharmacology, and Disease, Annu.Rev.Pharmacol.Toxicol.,
2010, pp. 295-322, 50. cited by applicant .
Schaffhauser et al, Pharmacological Characterization and
Identification of Amino Acids Involved in the Positive Modulation
of Metabotropic Glutamate Receptor Subtype 2, Molecular
Pharmacology, Jun. 13, 2003, pp. 798-810, vol. 64, No. 4. cited by
applicant.
|
Primary Examiner: Ward; Paul V
Claims
The invention claimed is:
1. A compound of Formula (I) ##STR00260## or a stereoisomeric form
or a tautomer thereof, wherein R.sup.1 is phenyl optionally
substituted with one or more substituents each independently
selected from the group consisting of halo, C.sub.1-4alkyl,
mono-haloC.sub.1-4alkyl, poly-halo-C.sub.1-4alkyl, --CN, and
C.sub.3-7cycloalkyl; R.sup.2 is selected from the group consisting
of H; C.sub.1-4alkyl; C.sub.3-7cycloalkyl; --CN; --NR.sup.aR.sup.b;
--C(O)NR.sup.cR.sup.d; --C(O)C.sub.1-4alkyl; --C.sub.1-4alkyl--OH;
--C.sub.1-4alkyl-O--C.sub.1-4alkyl; Aryl; Het; and C.sub.1-4alkyl
substituted with one or more substituents each independently
selected from the group consisting of halo and C.sub.3-7cycloalkyl;
wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each
independently selected from consisting of H and C.sub.1-4alkyl;
Aryl is phenyl optionally substituted with one or more substituents
each independently selected from the group consisting of halo,
C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl, and
poly-halo-C.sub.1-4alkyl; Het is (a) a 6-membered aromatic
heterocyclyl substituent selected from the group consisting of
pyridinyl, and pyrazinyl, each of which may be optionally
substituted with one or more substituents each independently
selected from the group consisting of halo, C.sub.1-4alkyl, and
--NR.sup.eR.sup.f; or (b) a 5-membered aromatic heterocyclyl
selected from the group consisting of thiazolyl, oxazolyl,
1H-pyrazolyl, and 1H-imidazolyl, each of which may be optionally
substituted with one or more substituents each independently
selected from the group consisting of halo, C.sub.1-4alkyl,
mono-haloC.sub.1-4alkyl, and poly-halo-C.sub.1-4alkyl; R.sup.e and
R.sup.f are each independently selected from consisting of
hydrogen, and C.sub.1-4alkyl; R.sup.3 is selected from the group
consisting of hydrogen, halo, C.sub.1-4alkyl, C.sub.3-7cycloalkyl,
--CN, and --OC.sub.1-4alkyl; R.sup.4 is selected from the group
consisting of hydrogen and C.sub.1-4alkyl; and R.sup.5 is selected
from the group consisting of hydrogen, C.sub.1-4alkyl, and
-C.sub.1-4alkyl-O--C.sub.1-4alkyl; or an N-oxide, or a
pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R.sup.1 is phenyl
optionally substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl, poly-halo-C.sub.1-4alkyl,
and --CN; R.sup.2 is selected from the group consisting of H;
C.sub.1-4alkyl; C.sub.3-7cycloalkyl; --CN; --NR.sup.aR.sup.b;
--C(O)NR.sup.cR.sup.d; --C.sub.1-4alkyl-O--C.sub.1-4alkyl; Aryl;
Het; and C.sub.1-4alkyl substituted with one or more substituents
each independently selected from halo; wherein R.sup.a, R.sup.b,
R.sup.c, and R.sup.d are each independently selected from H and
C.sub.1-4alkyl; Aryl is phenyl; Het is (a) pyridinyl optionally
substituted with a --NR.sup.eR.sup.f or a C.sub.1-4alkyl
substituent; R.sup.e and R.sup.f are each hydrogen; R.sup.3 is
selected from the group of hydrogen, halo, C.sub.1-4alkyl and
cyano; R.sup.4 is hydrogen; and R.sup.5 is C.sub.1-4alkyl; or an
N-oxide, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein R.sup.1 is phenyl
optionally substituted with one or two substituents each
independently selected from the group consisting of halo,
mono-haloC.sub.1-4alkyl, and poly-haloC.sub.1-4alkyl; R.sup.2 is
selected from the group consisting of C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; and C.sub.1-4alkyl substituted with one or
more substituents each independently selected from halo; R.sup.3 is
hydrogen; R.sup.4 is hydrogen; and R.sup.5 is C.sub.1-4alkyl; or an
N-oxide, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, having the formula (I') ##STR00261##
wherein the 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core,
R.sup.1 and the imidazole substituent are in the plane of the
drawing, R.sup.4 is hydrogen and R.sup.5 is projected above the
plane of the drawing.
5. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1 and a
pharmaceutically acceptable carrier or excipient.
6. A process for preparing the pharmaceutical composition,
comprising intimately mixing a pharmaceutically acceptable carrier
with a therapeutically effective amount of a compound of claim
1.
7. A method of treating a subject having a central nervous system
disorder or condition selected from the group consisting of mood
disorders; delirium, dementia, amnestic and other cognitive
neurocognitive disorders; disorders usually first diagnosed in
infancy, childhood or adolescence substance-related disorders;
schizophrenia, psychotic disorders other than schizophrenia;
somatoform disorders; and hypersomnic sleep disorder comprising
administering to said subject, a therapeutically effective amount
of a compound of claim 1.
8. A method of treating a subject having a central nervous system
disorder or condition selected from the group consisting of
depressive disorders; neurocognitive disorders; neurodevelopmental
disorders; substance-related and addictive disorders; schizophrenia
spectrum and other psychotic disorders; somatic symptom and related
disorders; and hypersomnolence disorder; comprising administering
to said subject, a therapeutically effective amount of a compound
of claim 1.
9. The method of claim 7 wherein the central nervous system
conditions or a diseases is schizophrenia.
10. The method of claim 7 wherein the disorders usually first
diagnosed in infancy, childhood or adolescence is
deficit/hyperactivity disorder.
11. The method of claim 8, wherein the depressive disorders are
selected from the group consisting of, major depressive disorder,
depression, and treatment resistant depression.
12. The method of claim 7 wherein additionally administered is an
additional pharmaceutical agent, as a combined preparation for
simultaneous, separate or sequential administration.
13. The method according to claim 7 or 8 wherein the central
nervous system conditions or diseases are selected from the group
consisting of dementia or neurocognitive disorder, major depressive
disorder, depression, treatment resistant depression,
attention-deficit/hyperactivity disorder and schizophrenia.
14. The method of claim 8 wherein additionally administered is an
additional pharmaceutical agent, as a combined preparation for
simultaneous, separate or sequential administration.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage of PCT Application No.
PCT/EP2015/078285, filed Dec. 2, 2015, which claims priority from
European Patent Application No. 14196082.3, filed Dec. 3, 2014, the
entire disclosures of which are hereby incorporated in their
entirety.
FIELD OF THE INVENTION
The present invention relates to novel
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as negative
allosteric modulators (NAMs) of the metabotropic glutamate receptor
subtype 2 ("mGluR2"). The invention is also directed to
pharmaceutical compositions comprising such compounds, to processes
for preparing such compounds and compositions, and to the use of
such compounds and compositions for the prevention or treatment of
disorders in which the mGluR2 subtype of metabotropic receptors is
involved.
BACKGROUND OF THE INVENTION
The glutamatergic system in the CNS is one of the neurotransmitter
systems that play a key role in several brain functions.
Metabotropic glutamate receptors (mGluR) belong to the
G-protein-coupled family, and eight different subtypes have been
identified to date, which are distributed to various brain regions
(Ferraguti & Shigemoto, Cell & Tissue Research,
326:483-504, 2006). mGluRs participate in the modulation of
synaptic transmission and neuronal excitability in the CNS by the
binding of glutamate. This activates the receptor to engage
intracellular signaling partners, leading to cellular events
(Niswender & Conn, Annual Review of Pharmacology &
Toxicology 50:295-322, 2010).
mGluRs are further divided into three subgroups based on their
pharmacological and structural properties: group-I (mGluR1 and
mGluR5), group-II (mGluR2 and mGluR3) and group-III (mGluR4,
mGluR6, mGluR7 and mGluR8). Group-II ligands, both orthosteric and
allosteric modulating, are considered to be potentially useful in
the treatment of various neurological disorders, including
psychosis, mood disorders, Alzheimer's disease and cognitive or
memory deficiencies. This is consistent with their primary
localisation in brain areas such as the cortex, hippocampus and the
striatum (Ferraguti & Shigemoto, Cell & Tissue Research
326:483-504, 2006). Particularly antagonists and negative
allosteric modulators are reported to hold potential for the
treatment of mood disorders and cognitive or memory dysfunction.
This is based on findings with group-II receptor antagonists and
negative allosteric modulators tested in laboratory animals
subjected to a range of experimental conditions deemed relevant to
these clinical syndromes (Goeldner et al, Neuropharmacology
64:337-346, 2013). Clinical trials are, for example, underway with
mGluR2/3 antagonist declogurant RO4995819 (F. Hoffmann-La Roche
Ltd.) in adjunctive therapy in patients with Major Depressive
Disorder having inadequate response to ongoing antidepressant
treatment (ClinicalTrials.gov Identifier NCT01457677, retrieved 19
Feb. 2014).
WO 2013066736 (Merck Sharp & Dohme Corp.) describes quinoline
carboxamide and quinoline carbonitrile compounds as mGluR2 NAMs.
WO2013174822 (Domain Therapeutics) describes
4H-pyrazolo[1,5-a]quinazolin-5-ones and
4H-pyrrolo-[1,2-a]quinazolin-5-ones and in vitro mGluR2 NAM
activity thereof. WO 2014064028 (F. Hoffman-La Roche AG) discloses
a selection of mGlu2/3 negative allosteric modulators and their
potential use in the treatment of Autistic Spectrum Disorders
(ASD).
The group-II receptors are mainly located on presynaptic nerve
terminals where they exert a negative feedback loop to the release
of glutamate into the synapse (Kelmendi et al, Primary Psychiatry
13:80-86, 2006). Functional inhibition of these receptors by
antagonists or negative allosteric modulators therefore lifts the
brake on glutamate release, resulting in enhanced glutamatergic
signaling. This effect is believed to underlie the
antidepressant-like and procognitive effects observed in
preclinical species with inhibitors of the Group-II receptor. In
addition, treatment of mice with group-II orthosteric antagonists
has been shown to enhance signaling by growth factors such as brain
derived neurotrophic factor (BDNF) (Koike et al, Behavioural Brain
Research 238:48-52, 2013). Since BDNF and other growth factors have
been shown to be critically involved in mediating synaptic
plasticity, this mechanism is likely to contribute to both
antidepressant and procognitive properties of these compounds.
Inhibition of mGluRs of the group-II receptor family is therefore
considered to represent a potential therapeutic mechanism for
neurological disorders, including depression and cognitive or
memory dysfunction.
DESCRIPTION OF THE INVENTION
The present invention is directed to
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives of Formula
(I)
##STR00001## and stereoisomeric forms and tautomers thereof,
wherein
R.sup.1 is phenyl optionally substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl,
poly-halo-C.sub.1-4alkyl, --CN, and C.sub.3-7cycloalkyl;
R.sup.2 is selected from the group consisting of H; C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; --CN; --NR.sup.aR.sup.b;
--C(O)NR.sup.cR.sup.d; --C(O)C.sub.1-4alkyl; --C.sub.1-4alkyl-OH;
--C.sub.1-4alkyl-O--C.sub.1-4alkyl; Aryl; Het; and C.sub.1-4alkyl
substituted with one or more substituents each independently
selected from the group consisting of halo and C.sub.3-7cycloalkyl;
wherein
R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each independently
selected from H and C.sub.1-4alkyl;
Aryl is phenyl optionally substituted with one or more substituents
each independently selected from the group consisting of halo,
C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl, and
poly-halo-C.sub.1-4alkyl;
Het is (a) a 6-membered aromatic heterocyclyl substituent selected
from the group consisting of pyridinyl, and pyrazinyl, each of
which may be optionally substituted with one or more substituents
each independently selected from the group consisting of halo,
C.sub.1-4alkyl, and --NR.sup.eR.sup.f;
or (b) a 5-membered aromatic heterocyclyl selected from the group
consisting of thiazolyl, oxazolyl, 1H-pyrazolyl, and 1H-imidazolyl,
each of which may be optionally substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl, and
poly-halo-C.sub.1-4alkyl;
R.sup.e and R.sup.f are each independently selected from hydrogen,
and C.sub.1-4alkyl; and
R.sup.3 is selected from the group consisting of hydrogen, halo,
C.sub.1-4alkyl, C.sub.3-7cycloalkyl, --CN, and
--OC.sub.1-4alkyl;
R.sup.4 is selected from hydrogen and C.sub.1-4alkyl;
R.sup.5 is selected from the group consisting of hydrogen,
C.sub.1-4alkyl, and --C.sub.1-4alkyl-O--C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
The present invention also relates to a pharmaceutical composition
comprising a therapeutically effective amount of a compound of
Formula (I) and a pharmaceutically acceptable carrier or
excipient.
Additionally, the invention relates to a compound of Formula (I)
for use as a medicament, and to a compound of Formula (I) for use
in the treatment or in the prevention of central nervous system
conditions or diseases selected from mood disorders; delirium,
dementia, amnestic and other cognitive disorders; disorders usually
first diagnosed in infancy, childhood or adolescence;
substance-related disorders; schizophrenia and other psychotic
disorders; somatoform disorders; and hypersomnic sleep
disorder.
The invention also relates to the use of a compound of Formula (I)
in combination with an additional pharmaceutical agent for use in
the treatment or prevention of central nervous system conditions or
diseases selected from mood disorders; delirium, dementia, amnestic
and other cognitive disorders; disorders usually first diagnosed in
infancy, childhood or adolescence; substance-related disorders;
schizophrenia and other psychotic disorders; somatoform disorders;
and hypersomnic sleep disorder.
Furthermore, the invention relates to a process for preparing a
pharmaceutical composition according to the invention,
characterized in that a pharmaceutically acceptable carrier is
intimately mixed with a therapeutically effective amount of a
compound of Formula (I).
The invention also relates to a method of treating or preventing a
central nervous system disorder selected from mood disorders;
delirium, dementia, amnestic and other cognitive disorders;
disorders usually first diagnosed in infancy, childhood or
adolescence; substance-related disorders; schizophrenia and other
psychotic disorders; somatoform disorders; and hypersomnic sleep
disorder comprising administering to a subject in need thereof, a
therapeutically effective amount of a compound of Formula (I) or a
therapeutically effective amount of a pharmaceutical composition
according to the invention.
The invention also relates to a product comprising a compound of
Formula (I) and an additional pharmaceutical agent, as a combined
preparation for simultaneous, separate or sequential use in the
treatment or prevention of central nervous system conditions or
diseases selected from mood disorders; delirium, dementia, amnestic
and other cognitive disorders; disorders usually first diagnosed in
infancy, childhood or adolescence; substance-related disorders;
schizophrenia and other psychotic disorders; somatoform disorders;
and hypersomnic sleep disorder.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates in particular to compounds of Formula
(I) as defined hereinabove, and stereoisomeric forms and tautomers
thereof, wherein
R.sup.1 is phenyl optionally substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl,
poly-halo-C.sub.1-4alkyl, and --CN;
R.sup.2 is selected from the group consisting of H; C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; --CN; --NR.sup.aR.sup.b;
--C(O)NR.sup.cR.sup.d; --C.sub.1-4alkyl-O--C.sub.1-4alkyl; Aryl;
Het; and C.sub.1-4alkyl substituted with one or more substituents
each independently selected from halo; wherein
R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each independently
selected from H and C.sub.1-4alkyl;
Aryl is phenyl;
Het is (a) pyridinyl optionally substituted with a
--NR.sup.eR.sup.f or a C.sub.1-4alkyl substituent;
R.sup.e and R.sup.f are each hydrogen;
R.sup.3 is selected from the group of hydrogen, halo,
C.sub.1-4alkyl and cyano;
R.sup.4 is hydrogen; and
R.sup.5 is C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
In a further embodiment, the invention relates to compounds of
Formula (I) as defined hereinabove, and stereoisomeric forms
thereof, wherein
R.sup.1 is phenyl optionally substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-4alkyl, mono-haloC.sub.1-4alkyl,
poly-halo-C.sub.1-4alkyl, and --CN;
R.sup.2 is selected from the group consisting of H; C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; --CN; --NR.sup.aR.sup.b;
--C(O)NR.sup.cR.sup.d; --C.sub.1-4alkyl-O--C.sub.1-4alkyl; Aryl;
Het; and C.sub.1-4alkyl substituted with one or more substituents
each independently selected from halo; wherein
R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each independently
selected from H and C.sub.1-4alkyl;
Aryl is phenyl;
Het is (a) pyridinyl optionally substituted with a
--NR.sup.eR.sup.f or a C.sub.1-4alkyl substituent;
R.sup.e and R.sup.f are each hydrogen;
R.sup.3 is selected from the group consisting of hydrogen, halo,
and C.sub.1-4alkyl;
R.sup.4 is hydrogen; and
R.sup.5 is C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
In a further embodiment, the invention relates to compounds of
Formula (I) as defined hereinabove, and stereoisomeric forms
thereof, wherein
R.sup.1 is phenyl optionally substituted with one or two
substituents each independently selected from the group consisting
of halo, mono-haloC.sub.1-4alkyl, and poly-halo-C.sub.1-4alkyl;
R.sup.2 is selected from the group consisting of C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; and C.sub.1-4alkyl substituted with one or
more substituents each independently selected from halo;
R.sup.3 is hydrogen;
R.sup.4 is hydrogen; and
R.sup.5 is C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
In a further embodiment, the invention relates to compounds of
Formula (I) as defined hereinabove, and stereoisomeric forms
thereof, wherein
R.sup.1 is phenyl substituted with one or two substituents each
independently selected from the group consisting of halo,
mono-haloC.sub.1-4alkyl, and poly-haloC.sub.1-4alkyl;
R.sup.2 is selected from the group consisting of C.sub.1-4alkyl;
C.sub.3-7cycloalkyl; and C.sub.1-4alkyl substituted with one or
more substituents each independently selected from halo;
R.sup.3 is hydrogen;
R.sup.4 is hydrogen; and
R.sup.5 is C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
In a further embodiment, the invention relates to compounds of
Formula (I) as defined hereinabove, and stereoisomeric forms
thereof, wherein
R.sup.1 is phenyl substituted with one or two substituents each
independently selected from the group consisting of halo,
mono-haloC.sub.1-4alkyl, and poly-haloC.sub.1-4alkyl;
R.sup.2 is selected from the group consisting of C.sub.1-4alkyl;
and C.sub.1-4alkyl substituted with one or more substituents each
independently selected from halo;
R.sup.3 is hydrogen;
R.sup.4 is hydrogen; and
R.sup.5 is C.sub.1-4alkyl;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and the solvates thereof.
In a further embodiment, the invention relates to compounds of
Formula (I) as defined herein, and stereoisomeric forms thereof,
wherein R.sup.2 is C.sub.1-4alkyl and the rest of variables are as
defined herein.
In a further embodiment, the present invention relates to compounds
of Formula (I) as defined herein wherein R.sup.4 is hydrogen and
R.sup.5 is a substituent different from hydrogen having a
configuration as depicted in the Formula (I') below, wherein the
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core, R.sup.1 and the
imidazole substituent are in the plane of the drawing and R.sup.5
is projected above the plane of the drawing (bond shown with a bold
wedge), and the rest of variables are as defined in Formula (I)
herein
##STR00002##
In a yet further embodiment, the present invention relates to
compounds of Formula (I) as defined herein wherein R.sup.5 is
hydrogen and R.sup.4 is a substituent different from hydrogen, for
example a C.sub.1-4alkyl substituent having a configuration as
depicted in the Formula (I'') below, wherein the
6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one core, R.sup.1 and the
imidazole substituent are in the plane of the drawing and R.sup.4
is projected above the plane of the drawing (bond shown with a bold
wedge), and the rest of variables are as defined in Formula (I)
herein
##STR00003##
Specific compounds according to the invention include:
(7S)-7-methyl-3-(2-methyl-1H-imidazol-4-yl)-5-[4-(trifluoromethyl)phenyl]-
-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-(2-methyl-1H-imida-
zol-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(1H-imidazol-4-yl)-7-methyl-5-[4-(trifluoromethyl)phenyl]-6,7-dihy-
dropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(5-bromo-1H-imidazol-4-yl)-7-methyl-5-[4-(trifluoromethyl)phenyl]--
6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(2-cyclopropyl-1H-imidazol-4-yl)-7-methyl-5-[4-(trifluoromethyl)ph-
enyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2-cyclopropyl-1H-imidazol--
4-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2-isopropyl-1H-imidazol-4--
yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(2-isopropyl-1H-imidazol-4-yl)-7-methyl-5-[4-(trifluoromethyl)phen-
yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
4-[(7S)-7-methyl-4-oxo-5-[4-(trifluoromethyl)phenyl]-6,7-dihydropyrazolo[-
1,5-a]pyrazin-3-yl]-1H-imidazole-2-carbonitrile;
4-[(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydro-
pyrazolo[1,5-a]pyrazin-3-yl]-1H-imidazole-2-carbonitrile;
(7S)-7-methyl-3-[2-(methylamino)-1H-imidazol-5-yl]-5-[4-(trifluoromethyl)-
phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(methoxymethyl)-1H-imidazol-5-yl]-7-methyl-5-[4-(trifluoromethy-
l)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
5-[(7S)-7-methyl-3-(2-methyl-1H-imidazol-4-yl)-4-oxo-6,7-dihydropyrazolo[-
1,5-a]pyrazin-5-yl]-2-(trifluoromethyl)benzonitrile;
(7S)-7-methyl-3-[2-(trifluoromethyl)-1H-imidazol-5-yl]-5-[4-(trifluoromet-
hyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
4-[(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydro-
pyrazolo[1,5-a]pyrazin-3-yl]-1H-imidazole-2-carboxamide;
4-[(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydro-
pyrazolo[1,5-a]pyrazin-3-yl]-N-methyl-1H-imidazole-2-carboxamide;
4-[(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-4-oxo-6,7-dihydro-
pyrazolo[1,5-a]pyrazin-3-yl]-N,N-dimethyl-1H-imidazole-2-carboxamide;
(7S)-7-methyl-3-(2-phenyl-1H-imidazol-4-yl)-5-[4-(trifluoromethyl)phenyl]-
-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2,4-dimethyl-1H-imidazol-5-
-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2-cyclopropyl-4-methyl-1H--
imidazol-5-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-5-bromo-1H-imidazol-4-yl]-7-methyl-5-[4-(tr-
ifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-(fluoromethyl)-4-(trifluoromethyl)phenyl]-7-methyl-3-(2-methyl--
1H-imidazol-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-[5-methyl-2-(3-pyr-
idyl)-1H-imidazol-4-yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-1H-imidazol-4-yl]-7-methyl-5-[4-(trifluorom-
ethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-7-methyl-5-[4-(trifluoro-
methyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-5-methyl-1H-imidazol-4-yl]-7-methyl-5-[4-(t-
rifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-5-methyl-1H-imidazol-4-yl]-5-[3-chloro-4-(t-
rifluoromethyl)phenyl]-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-1H-imidazol-4-yl]-5-[3-chloro-4-(trifluorom-
ethyl)phenyl]-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-5-chloro-1H-imidazol-4-yl]-7-methyl-5-[4-(t-
rifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-7-methyl-3-[5-methyl-2-(3-pyridyl)-1H-imidazol-4-yl]-5-[4-(trifluoro-
methyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-1H-imidazol-4-yl]-7-methyl-5-[3-methyl-4-(t-
rifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-7-methyl-3-[5-methyl-2-(2-pyridyl)-1H-imidazol-4-yl]-5-[4-(trifluoro-
methyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-[2-(6-amino-3-pyridyl)-1H-imidazol-4-yl]-5-(3,4-dichlorophenyl)-7--
methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-[2-(2-pyridyl)-1H--
imidazol-4-yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-7-methyl-5-[3-methyl-4-(trifluoromethyl)phenyl]-3-[2-(2-pyridyl)-1H--
imidazol-4-yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-[5-methyl-2-(2-pyr-
idyl)-1H-imidazol-4-yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-7-methyl-5-[3-methyl-4-(-
trifluoromethyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-[2-(3-pyridyl)-1H--
imidazol-4-yl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-(3,4-dichlorophenyl)-7-methyl-3-[2-(2-pyridyl)-1H-imidazol-4-yl]-6-
,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-7-methyl-3-[2-(2-methyl-4-pyridyl)-1H-imidazol-5-yl]-5-[4-(trifluoro-
methyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-3-(2-cyclobutyl-1H-imidazol-5-yl)-7-methyl-5-[4-(trifluoromethyl)phe-
nyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
2-(6-amino-3-pyridyl)-4-[(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-me-
thyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-3-yl]-1H-imidazole-5-carbonit-
rile;
(7S)-7-methyl-3-(2-pyrazin-2-yl-1H-imidazol-4-yl)-5-[4-(trifluoromet-
hyl)phenyl]-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-7-methyl-3-(2-pyrazin-2-yl-1H-
-imidazol-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2-cyclobutyl-1H-imidazol-5-
-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one;
and the N-oxides thereof, and the pharmaceutically acceptable salts
and solvates of such compounds.
In an additional embodiment, the compound is
(7S)-5-[3-chloro-4-(trifluoromethyl)phenyl]-3-(2,4-dimethyl-1H-imidazol-5-
-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4-one or a
hydrochloride salt thereof.
The names of the compounds of the present invention were generated
according to the nomenclature rules agreed upon by the
International Union of Pure and Applied Chemistry (IUPAC) generated
by Accelrys Direct, Revision 8.0 SP1 (Microsoft Windows 64-bit
Oracle11) (8.0.100.4), OpenEye:1.2.0. In case of tautomeric forms,
the name of the depicted tautomeric form of the structure was
generated. However it should be clear that the other non-depicted
tautomeric form is also included within the scope of the present
invention.
Definitions
The notation "C.sub.1-4alkyl" as used herein alone or as part of
another group, defines a saturated, straight or branched,
hydrocarbon radical having, unless otherwise stated, from 1 to 4
carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl,
butyl, 1-methyl-propyl, 2-methyl-1-propyl, 1,1-dimethylethyl and
the like. The notation "--C.sub.1-4alkyl-OH" as used herein alone
or as part of another group, refers to C.sub.1-4alkyl as defined
before, substituted with one OH group at any available carbon atom.
The notation "halogen" or "halo" as used herein alone or as part of
another group, refers to fluoro, chloro, bromo or iodo, with fluoro
or chloro being preferred. The notation "mono-haloC.sub.1-4alkyl,
polyhaloC.sub.1-4alkyl" as used herein alone or as part of another
group, refers to C.sub.1-4alkyl as defined before, substituted with
1, 2, 3 or where possible with more halo atoms as defined before.
The notation "C.sub.3-7cycloalkyl" as used herein refers to a
saturated, cyclic hydrocarbon radical having from 3 to 7 carbon
atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl. A particular C.sub.3-7cycloalkyl group is
cyclopropyl.
The N-oxide forms of the compounds according to Formula (I) are
meant to comprise those compounds of Formula (I) wherein one or
several nitrogen atoms are oxidized to the so called N-oxide,
particularly those N-oxides wherein a nitrogen atom in a pyridinyl
radical is oxidized. N-oxides can be formed following procedures
known to the skilled person. The N-oxidation reaction may generally
be carried out by reacting the starting material of Formula (I)
with an appropriate organic or inorganic peroxide. Appropriate
inorganic peroxides comprise, for example, hydrogen peroxide,
alkali metal or alkaline metal peroxides, e.g. sodium peroxide,
potassium peroxide/appropriate organic peroxides may comprise
peroxy acids such as, for example, benzenecarboperoxoic acid or
halo substituted benzenecarboperoxoic acid, e.g.
3-chloroperoxybenzoic acid (or 3-chloroperbenzoic acid),
peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,
e.g. tert-butyl hydroperoxide. Suitable solvents, are for example,
water, lower alkanols, e.g. ethanol and the like, hydrocarbons,
e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons,
e.g. dichloromethane, and mixtures of such solvents.
Whenever the term "substituted" is used in the present invention,
it is meant, unless otherwise is indicated or is clear from the
context, to indicate that one or more hydrogens, preferably from 1
to 3 hydrogens, more preferably from 1 to 2 hydrogens, more
preferably 1 hydrogen, on the atom or radical indicated in the
expression using "substituted" are replaced with a selection from
the indicated group, provided that the normal valency is not
exceeded, and that the substitution results in a chemically stable
compound, i.e. a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into a therapeutic agent.
The term "subject" as used herein, refers to an animal, preferably
a mammal, most preferably a human, who is or has been the object of
treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means
that amount of active compound or pharmaceutical agent that elicits
the biological or medicinal response in a tissue system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician, which includes alleviation of the
symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combinations of the specified ingredients in the
specified amounts.
It will be appreciated that some of the compounds of Formula (I)
and their pharmaceutically acceptable addition salts and solvates
thereof may contain one or more centres of chirality and exist as
stereoisomeric forms. The term "compounds of the invention" as used
herein, is meant to include the compounds of Formula (I), and the
salts and solvates thereof. As used herein, any chemical formula
with bonds shown only as solid lines and not as solid wedged or
hashed wedged bonds, or otherwise indicated as having a particular
configuration (e.g. R, S) around one or more atoms, contemplates
each possible stereoisomer, or mixture of two or more
stereoisomers. Hereinbefore and hereinafter, the term "compound of
Formula (I)" is meant to include the stereoisomers thereof and the
tautomeric forms thereof. The terms "stereoisomers",
"stereoisomeric forms" or "stereochemically isomeric forms"
hereinbefore or hereinafter are used interchangeably. The invention
includes all stereoisomers of the compounds of the invention either
as a pure stereoisomer or as a mixture of two or more
stereoisomers. Enantiomers are stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a racemate or racemic mixture. Diastereomers
(or diastereoisomers) are stereoisomers that are not enantiomers,
i.e. they are not related as mirror images. If a compound contains
a double bond, the substituents may be in the E or the Z
configuration. Substituents on bivalent cyclic (partially)
saturated radicals may have either the cis- or trans-configuration;
for example if a compound contains a disubstituted cycloalkyl
group, the substituents may be in the cis or trans configuration.
Therefore, the invention includes enantiomers, diastereomers,
racemates, E isomers, Z isomers, cis isomers, trans isomers and
mixtures thereof, whenever chemically possible. The meaning of all
those terms, i.e. enantiomers, diastereomers, racemates, E isomers,
Z isomers, cis isomers, trans isomers and mixtures thereof are
known to the skilled person.
The absolute configuration is specified according to the
Cahn-Ingold-Prelog system. The configuration at an asymmetric atom
is specified by either R or S. Resolved stereoisomers whose
absolute configuration is not known can be designated by (+) or (-)
depending on the direction in which they rotate plane polarized
light. For instance, resolved enantiomers whose absolute
configuration is not known can be designated by (+) or (-)
depending on the direction in which they rotate plane polarized
light.
When a specific stereoisomer is identified, this means that said
stereoisomer is substantially free, i.e. associated with less than
50%, preferably less than 20%, more preferably less than 10%, even
more preferably less than 5%, in particular less than 2% and most
preferably less than 1%, of the other isomers. Thus, when a
compound of Formula (I) is for instance specified as (R), this
means that the compound is substantially free of the (S) isomer;
when a compound of Formula (I) is for instance specified as E, this
means that the compound is substantially free of the Z isomer; when
a compound of Formula (I) is for instance specified as cis, this
means that the compound is substantially free of the trans
isomer.
Some of the compounds according to Formula (I) may also exist in
their tautomeric form. Such forms in so far as they may exist,
although not explicitly indicated in the above formula are intended
to be included within the scope of the present invention. It
follows that a single compound may exist in both stereoisomeric and
tautomeric forms.
For therapeutic use, salts of the compounds of Formula (I) are
those wherein the counterion is pharmaceutically acceptable.
However, salts of acids and bases which are non-pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound. All salts,
whether pharmaceutically acceptable or not, are included within the
ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as
mentioned hereinabove or hereinafter are meant to comprise the
therapeutically active non-toxic acid and base addition salt forms
which the compounds of Formula (I) are able to form. The
pharmaceutically acceptable acid addition salts can conveniently be
obtained by treating the base form with such appropriate acid.
Appropriate acids comprise, for example, inorganic acids such as
hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,
nitric, phosphoric and the like acids; or organic acids such as,
for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,
oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic
acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic,
ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic,
salicylic, p-aminosalicylic, pamoic and the like acids. Conversely
said salt forms can be converted by treatment with an appropriate
base into the free base form. The compounds of Formula (I)
containing an acidic proton may also be converted into their
non-toxic metal or amine addition salt forms by treatment with
appropriate organic and inorganic bases. Appropriate base salt
forms comprise, for example, the ammonium salts, the alkali and
earth alkaline metal salts, e.g. the lithium, sodium, potassium,
magnesium, calcium salts and the like, salts with organic bases,
e.g. primary, secondary and tertiary aliphatic and aromatic amines
such as methylamine, ethylamine, propylamine, isopropylamine, the
four butylamine isomers, dimethylamine, diethylamine,
diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine,
pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine,
tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline;
the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts
with amino acids such as, for example, arginine, lysine and the
like. Conversely the salt form can be converted by treatment with
acid into the free acid form.
The term solvate comprises the solvent addition forms as well as
the salts thereof, which the compounds of Formula (I) are able to
form. Examples of such solvent addition forms are e.g. hydrates,
alcoholates and the like.
In the framework of this application, an element, in particular
when mentioned in relation to a compound according to Formula (I),
comprises all isotopes and isotopic mixtures of this element,
either naturally occurring or synthetically produced, either with
natural abundance or in an isotopically enriched form, for example
.sup.2H.
Radiolabelled compounds of Formula (I) may comprise a radioactive
isotope selected from the group consisting of .sup.3H, .sup.11C,
.sup.14C, .sup.18F, .sup.122I, .sup.123I, .sup.125, .sup.131I,
.sup.75Br, .sup.76Br, .sup.77Br and .sup.82Br. Preferably, the
radioactive isotope is selected from the group consisting of
.sup.3H, .sup.11C and .sup.18F.
PREPARATION
The compounds according to the invention can generally be prepared
by a succession of steps, each of which is known to the skilled
person. In particular, the compounds can be prepared according to
the following synthesis methods.
The compounds of Formula (I) may be synthesized in the form of
racemic mixtures of enantiomers which can be separated from one
another following art-known resolution procedures. The racemic
compounds of Formula (I) may be converted into the corresponding
diastereomeric salt forms by reaction with a suitable chiral acid.
Said diastereomeric salt forms are subsequently separated, for
example, by selective or fractional crystallization and the
enantiomers are liberated therefrom by alkali. Said pure
stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically.
The absolute configuration of compounds of the invention reported
herein was determined by analysis of the racemic mixture by
supercritical fluid chromatography (SFC) followed by SFC comparison
of the separate enantiomer(s) which were obtained by asymmetric
synthesis, followed by vibrational circular dichroism (VCD)
analysis of the particular enantiomer(s).
A. Preparation of the Final Compounds
Experimental Procedure 1
Final compounds according to Formula (I) can be prepared by a
Suzuki type coupling reaction of a compound of Formula (II) where
R.sup.6a and R.sup.7a may be each independently selected from H,
C.sub.1-4alkyl or R.sup.6a and R.sup.7a may be taken together to
form for example a bivalent radical of formula
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2C(CH.sub.3).sub.2-- with a suitable halo
imidazole derivative compound of Formula (III) wherein X is a
halogen, in particular bromo or iodo, in the presence of a
palladium catalyst, according to reaction conditions known to the
skilled person. Such reaction conditions include the use of a
palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or an alternative catalyst
system prepared in situ from Pd(OAc).sub.2 and PPh.sub.3, a
suitable base, such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOAc,
NaHCO.sub.3 or K.sub.3PO.sub.4, and in a suitable solvent, such as
1,4-dioxane, or a mixture of dimethoxyethane (DME) and water.
Degassing the reaction mixture with an inert gas, such as N.sub.2
or argon, and heating the reaction mixture to high temperatures,
such as reflux temperature under classical heating or microwave
irradiation, in particular 80.degree. C., may enhance the reaction
outcome. A compound of Formula (III) can be obtained commercially
or made according to procedures known in the art. In Reaction
Scheme 1, all variables are defined as in Formula (I).
##STR00004##
Experimental Procedure 2
Alternatively, final compounds according to Formula (I) wherein
R.sup.3 is halo (R.sup.3=X) hereby referred to as compounds of
Formula (I-a) can be prepared via a reaction of halogenation of a
compound of Formula (I) wherein R.sup.3 is hydrogen (R.sup.3=H)
hereby referred to as compounds of Formula (I-b) with a
halogenating reagent such as N-bromosuccinimide, in an inert
solvent such as acetonitrile, under suitable reaction conditions,
such as at a convenient temperature, typically rt, for a period of
time to ensure the completion of the reaction. In Reaction Scheme
2, X is halo and all other variables are defined as in Formula
(I).
##STR00005##
Experimental Procedure 3
Alternatively, final compounds according to Formula (I) can be
prepared by a reaction of deprotection of a compound of Formula
(IV) according to conditions known to the skilled person. A
compound of Formula (I) can be obtained by removal of the
protecting group such as for example: a) A SEM
(trimethylsilyl)ethoxymethyl) protecting group in the compound of
Formula (IV), in the presence of acidic media, such as hydrochloric
acid in an inert solvent such as a 2-propanol, under suitable
reaction conditions, such as at a convenient temperature, typically
ranging between 50.degree. C. and 70.degree. C., in particular
60.degree. C., for a period of time to ensure the completion of the
reaction. Heating the reaction mixture under microwave irradiation,
in particular 100.degree. C., may enhance the reaction outcome. b)
A benzyloxymethyl group in the presence of a Lewis acid, such as
boron tribromide, in an inert solvent such as toluene, under
suitable reaction conditions, such as at a convenient temperature,
in particular at 90.degree. C., for a period of time to ensure the
completion of the reaction. c) A benzyl group by means of catalytic
hydrogenation in the presence of an appropriate catalyst, such as
palladium hydroxide, under hydrogen atmosphere, in an inert solvent
such as a mixture of EtOH/acetic acid, at a convenient temperature,
typically ranging between 90 to 110.degree. C., in particular
100.degree. C., for a period of time to ensure the completion of
the reaction. In Reaction Scheme 3, PG is a protecting group and
all other variables are defined as in Formula (I).
##STR00006##
Experimental Procedure 4
Alternatively, final compounds according to Formula (I) wherein
R.sup.2 is NHR.sup.b herein referred to as a compound of Formula
(I-c), can be prepared by one-pot two-step protocol from a compound
of Formula (V) following conditions described by D. S. Ermolat'ev
and al. in Mol Divers., 2011, 15(2), 491-6. This process involves
the sequential formation of
2,3-dihydro-2-hydroxyimidazo[1,2-a]pyrimidinium salts from an
.alpha.-bromoketone of Formula (V) and a compound of Formula (VI),
followed by cleavage of the pyrimidine ring with hydrazine. A
compound of Formula (VI) can be obtained commercially or made
according to procedures known in the art. In Reaction Scheme 4, all
variables are defined as in Formula (I).
##STR00007##
B. Preparation of the Intermediate Compounds
Experimental Procedure 5
Intermediate compound of Formula (II) can be prepared via a
reaction of boronic ester or boronic acid formation starting from
an intermediate of Formula (VII), with a trans metallating agent
such as for example nBuLi or a Grignard reagent, a particular
example of reagents includes isopropylmagnesium chloride lithium
chloride complex solution and a boron species such as
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, in an inert
solvent such as anhydrous THF, under suitable reaction conditions,
such as at a convenient temperature, typically -25.degree. C., for
a period of time to ensure the completion of the reaction.
Depending on reaction conditions, boronic ester and/or boronic acid
are obtained. In Reaction Scheme 5, R.sup.6a and R.sup.7a are H or
C.sub.1-4 alkyl or R.sup.6a and R.sup.7a are taken together to form
for example a bivalent radical of formula --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2C(CH.sub.3).sub.2--, and all other variables are
defined as in Formula (I).
##STR00008##
Experimental Procedure 6
Intermediate compound of Formula (VII) can be prepared via a
reaction of halogenation of an intermediate of Formula (VIII) with
a halogenating reagent such as iodine, in the presence of ammonium
cerium(IV) nitrate and in an inert solvent such as acetonitrile,
under suitable reaction conditions, such as at a convenient
temperature, typically 70.degree. C., for a period of time to
ensure the completion of the reaction. In Reaction Scheme 6, all
variables are defined as in Formula (I).
##STR00009##
Experimental Procedure 7
Intermediate compound of Formula (VIII) can be prepared by a
coupling reaction of an intermediate compound of Formula (IX) with
an appropriate aryl/heteroaryl halide of Formula (X) where X is
halo with a suitable copper(I) catalyst such as copper(I) iodide,
in the presence of a ligand, such as N,N-dimethylethylenediamine,
in the presence of a base, such as Na.sub.2CO.sub.3, in a suitable
solvent, such as toluene, under suitable reaction conditions, such
as at a convenient temperature, typically ranging between
100.degree. C. and 140.degree. C., for a period of time to ensure
the completion of the reaction. An intermediate compound of Formula
(X) can be obtained commercially. In Reaction Scheme 7, all
variables are defined as in Formula (I).
##STR00010##
Experimental Procedure 8
Intermediate compound of Formula (IX) can be prepared by removal of
the protecting group in an intermediate of Formula (XI), for
example in the presence of acidic media, such as hydrochloric acid,
in an inert solvent such as 1,4-dioxane, under suitable reaction
conditions, such as at a convenient temperature, typically
80.degree. C., for a period of time to ensure the completion of the
reaction followed by treatment with a base, such as
Na.sub.2CO.sub.3 or NaHCO.sub.3, under suitable reaction
conditions, such as at a convenient temperature, typically ranging
between 0.degree. C. and 40.degree. C., for a period of time to
ensure the completion of the reaction. In Reaction Scheme 8,
R.sup.8 is C.sub.1-4alkyl, PG is a protecting group and all other
variables are defined as in Formula (I).
##STR00011##
Experimental Procedure 9
Intermediate compound of Formula (XI) wherein R.sup.8 is
C.sub.1-4alkyl and PG is a protecting group, can be prepared by a
Mitsunobu type reaction between a compound of Formula (XII) and an
appropriate alcohol of Formula (XIII), in the presence of a
suitable triarylphosphine, such as triphenylphosphine, or a
suitable trialkylphosphine, and a suitable dialkyl azodicarboxylate
reagent, such as di-tert-butyl azodicarboxylate, in a suitable
inert solvent, such as THF, under suitable reaction conditions,
such as at a convenient temperature, typically rt, for a period of
time to ensure the completion of the reaction. Intermediate
compounds of Formula (XII) or Formula (XIII) can be obtained
commercially or synthesized according to literature procedures. In
Reaction Scheme 9, R.sup.8 is C.sub.1-4alkyl, PG is a protecting
group and all other variables are defined as in Formula (I).
##STR00012##
Experimental Procedure 10
Intermediate compound of Formula (IV) can be prepared by a Suzuki
type coupling reaction of a compound of Formula (II) where R.sup.6a
and R.sup.7a may be each independently selected from H,
C.sub.1-4alkyl or R.sup.6a and R.sup.7a may be taken together to
form for example a bivalent radical of formula
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2C(CH.sub.3).sub.2-- with a suitable N-protected
halo imidazole derivative compound of Formula (III-a) and X is a
halogen, in particular bromo or iodo, in the presence of a
palladium catalyst, according to reaction conditions known to the
skilled person. Such reaction conditions include the use of a
palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or an alternative catalyst
system prepared in situ from Pd(OAc).sub.2 and PPh.sub.3, a
suitable base, such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOAc,
NaHCO.sub.3 or K.sub.3PO.sub.4, and in a suitable solvent, such as
1,4-dioxane, or a mixture of dimethoxyethane (DME) and water.
Degassing the reaction mixture with an inert gas, such as N.sub.2
or argon, and heating the reaction mixture to high temperatures,
such as reflux temperature under classical heating or microwave
irradiation, in particular 80.degree. C., may enhance the reaction
outcome. A compound of Formula (III-a) can be obtained commercially
or made according to procedures known in the art. In Reaction
Scheme 10a, PG is a protecting group and all other variables are
defined as in Formula (I).
##STR00013##
In particular, an intermediate compound of Formula (IV) wherein
R.sup.2=X is halo, in particular chloro or bromo, and R.sup.3=H
hereby referred to as compounds of Formula (IV-a) can be prepared
by a Negishi type coupling reaction of a compound of Formula (VII)
with a suitable N-protected halo imidazole compound such as a
magnesium chloride derivative of Formula (III-b), in the presence
of a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) and a zinc species, such
as zinc chloride, in a suitable solvent, such as THF. In Reaction
Scheme 10b, X is halo (bromo or chloro), PG is a protecting group
and all other variables are defined as in Formula (I).
##STR00014##
Experimental Procedure 11
Intermediate compound of Formula (III-b) can be prepared by a
metalation process from a compound of Formula (III-c) following
conditions described by T. Petersen and al. in Angew. Chem. Int.
Ed. 2014, 53, 7933-7937. Performing the reaction under flow
conditions may enhance the reaction outcome.
Intermediate compound of Formula (III-c) can be prepared by a
reaction of protection of a compound of Formula (III-d) according
to conditions known to the skilled person. A compound of Formula
(III-d) can be obtained commercially or made according to
procedures known in the art. In Reaction Scheme 11, X is halo, in
particular chloro or bromo, and PG is a protecting group.
##STR00015##
Experimental Procedure 12
Intermediate compound of Formula (IV) can be prepared by a Suzuki
type coupling reaction of a compound of Formula (IV-a) with a
suitable boronate derivative or boronic acid, in the presence of a
palladium catalyst, according to reaction conditions known to the
skilled person. Such reaction conditions include the use of a
palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0) or an alternative catalyst
system prepared in situ from Pd(OAc).sub.2 and PPh.sub.3, a
suitable base, such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOAc,
NaHCO.sub.3 or K.sub.3PO.sub.4, and in a suitable solvent, such as
1,4-dioxane, or a mixture of dimethoxyethane (DME) and water.
Degassing the reaction mixture with an inert gas, such as N.sub.2
or argon, and heating the reaction mixture to high temperatures,
such as reflux temperature under classical heating or microwave
irradiation, in particular 90.degree. C., may enhance the reaction
outcome.
Alternatively, intermediate compound of Formula (IV) can be
prepared by a Negishi type coupling reaction of a compound of
Formula (IV-a) with a suitable zincate species in the presence of a
palladium catalyst, according to reaction conditions known to the
skilled person. In Reaction Scheme 12, PG is a protecting group and
all other variables are defined as in Formula (I).
##STR00016##
Experimental Procedure 13
Intermediate compound of Formula (V) can be prepared via a reaction
of halogenation of an intermediate of Formula (XIV) with a
halogenating reagent such as for example pyridinium tribromide, in
an inert solvent such as dichloromethane, under suitable reaction
conditions, such as at a convenient temperature, ranging between
0.degree. C. and 30.degree. C., for a period of time to ensure the
completion of the reaction.
Intermediate compound of Formula (XIV) can be prepared in a one pot
reaction. First a Stille type coupling reaction of a compound of
Formula (VII) with a suitable stannanyl compound of Formula (XV)
such as for example tributyl-(1-ethoxyvinyl)tin, in the presence of
a palladium catalyst such as bis(triphenylphosphine)palladium(II)
chloride, a suitable base, such as K.sub.2CO.sub.3 and in a
suitable solvent, such as a mixture of 1,4-dioxane and water under
suitable reaction conditions, such as at a convenient temperature,
typically 110.degree. C., for a period of time to ensure the
completion of the reaction. Then hydrolysis in acid media such as
for example with 2M aqueous solution of hydrochloric acid, under
suitable reaction conditions, such as at a convenient temperature,
typically 80.degree. C., for a period of time to ensure the
completion of the reaction. In Reaction Scheme 13, all variables
are defined as in Formula (I).
##STR00017##
In order to obtain the HCl salt forms of the compounds, several
procedures known to those skilled in the art can be used. In a
typical procedure, for example, the free base can be dissolved in
DIPE or Et.sub.2O and subsequently, a 6N HCl solution in 2-propanol
or a 1N HCl solution in Et.sub.2O can be added dropwise. The
mixture typically is stirred for 10 minutes after which the product
can be filtered off. The HCl salt usually is dried in vacuo.
It will be appreciated by those skilled in the art that in the
processes described above the functional groups of intermediate
compounds may need to be blocked by protecting groups. In case the
functional groups of intermediate compounds were blocked by
protecting groups, they can be deprotected after a reaction
step.
Pharmacology
The compounds provided in this invention are negative allosteric
modulators (NAMs) of metabotropic glutamate receptors, in
particular they are negative allosteric modulators of mGluR2. The
compounds of the present invention do not appear to bind to the
glutamate recognition site, the orthosteric ligand site, but
instead to an allosteric site within the seven transmembrane region
of the receptor. In the presence of glutamate, the compounds of
this invention decrease the mGluR2 response. The compounds provided
in this invention are expected to have their effect at mGluR2 by
virtue of their ability to decrease the response of such receptors
to glutamate, attenuating the response of the receptor.
As used herein, the term "treatment" is intended to refer to all
processes, wherein there may be a slowing, interrupting, arresting
or stopping of the progression of a disease or an alleviation of
symptoms, but does not necessarily indicate a total elimination of
all symptoms.
Hence, the present invention relates to a compound according to the
general Formula (I), or a stereoisomeric form thereof, or an
N-oxide thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof for use as a medicament.
The invention also relates to the use of a compound according to
the general Formula (I), or a stereoisomeric form thereof, or an
N-oxide thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, or a pharmaceutical composition according to
the invention for the manufacture of a medicament.
The invention also relates to a compound according to the general
Formula (I), or a stereoisomeric form thereof, or an N-oxide
thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, or a pharmaceutical composition according to
the invention for use in the treatment or prevention of, in
particular treatment of, a condition in a mammal, including a
human, the treatment or prevention of which is affected or
facilitated by the neuromodulatory effect of allosteric modulators
of mGluR2, in particular negative allosteric modulators
thereof.
The present invention also relates to the use of a compound
according to the general Formula (I), or a stereoisomeric form
thereof, or an N-oxide thereof, or a pharmaceutically acceptable
salt or a solvate thereof, in particular, a compound of Formula (I)
or a stereoisomeric form thereof, or a pharmaceutically acceptable
salt or a solvate thereof, or a pharmaceutical composition
according to the invention for the manufacture of a medicament for
the treatment or prevention of, in particular treatment of, a
condition in a mammal, including a human, the treatment or
prevention of which is affected or facilitated by the
neuromodulatory effect of allosteric modulators of mGluR2, in
particular negative allosteric modulators thereof.
The present invention also relates to a compound according to the
general Formula (I), or a stereoisomeric form thereof, or an
N-oxide thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, or a pharmaceutical composition according to
the invention for use in the treatment, prevention, amelioration,
control or reduction of the risk of various neurological and
psychiatric disorders associated with glutamate dysfunction in a
mammal, including a human, the treatment or prevention of which is
affected or facilitated by the neuromodulatory effect of negative
allosteric modulators of mGluR2.
Also, the present invention relates to the use of a compound
according to the general Formula (I), or a stereoisomeric form
thereof, or an N-oxide thereof, or a pharmaceutically acceptable
salt or a solvate thereof, in particular, a compound of Formula (I)
or a stereoisomeric form thereof, or a pharmaceutically acceptable
salt or a solvate thereof, or a pharmaceutical composition
according to the invention for the manufacture of a medicament for
treating, preventing, ameliorating, controlling or reducing the
risk of various neurological and psychiatric disorders associated
with glutamate dysfunction in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of negative allosteric modulators of
mGluR2.
In particular, the neurological and psychiatric disorders
associated with glutamate dysfunction, include one or more of the
following central nervous system conditions or diseases: mood
disorders; delirium, dementia, amnestic and other cognitive
disorders; disorders usually first diagnosed in infancy, childhood
or adolescence; substance-related disorders; schizophrenia and
other psychotic disorders; somatoform disorders; and hypersomnic
sleep disorder.
In particular, the central nervous system disorder is a psychotic
disorder selected from the group of schizophrenia (in particular in
antipsychotic-stabilized patients), schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic
disorder, and substance-induced psychotic disorder.
In particular, the central nervous system disorder is a
substance-related disorder selected from the group of alcohol
dependence, alcohol abuse, amphetamine dependence, amphetamine
abuse, caffeine dependence, caffeine abuse, cannabis dependence,
cannabis abuse, cocaine dependence, cocaine abuse, hallucinogen
dependence, hallucinogen abuse, nicotine dependence, nicotine
abuse, opioid dependence, opioid abuse, phencyclidine dependence,
and phencyclidine abuse.
In particular, the central nervous system disorder is a mood
disorder selected from the group of major depressive disorder,
depression, treatment resistant depression, dysthymic disorder,
cyclothymic disorder, and substance-induced mood disorder.
In particular, the central nervous system disorder is a disorder
usually first diagnosed in infancy, childhood, or adolescence
selected from mental retardation, learning disorder, motor skills
disorder, communication disorder, attention-deficit and disruptive
behaviour disorders (such as Attention-Deficit/Hyperactivity
Disorder (ADHD)). An additional disorder usually first diagnosed in
infancy, childhood, or adolescence is autistic disorder.
In particular, the central nervous system disorder is a cognitive
disorder selected from the group of dementia, in particular,
dementia of the Alzheimer's type, vascular dementia, dementia due
to HIV disease, dementia due to head trauma, dementia due to
Parkinson's disease, dementia due to Huntington's disease, dementia
due to Pick's disease, dementia due to Creutzfeldt-Jakob disease,
and substance-induced persisting dementia.
In particular, the central nervous system disorder is an amnestic
disorder, such as substance-induced persisting amnestic
disorder.
As already mentioned hereinabove, the term "treatment" does not
necessarily indicate a total elimination of all symptoms, but may
also refer to symptomatic treatment in any of the disorders
mentioned above. In particular, symptoms that may be treated
include but are not limited to, memory impairment in particular in
dementia or in major depressive disorder, age-related cognitive
decline, mild cognitive impairment, and depressive symptoms.
Of the disorders mentioned above, the treatment of dementia, major
depressive disorder, depression, treatment resistant depression,
attention-deficit/hyperactivity disorder and schizophrenia, in
particular in antipsychotic-stabilized patients, are of particular
importance.
The fourth edition of the Diagnostic & Statistical Manual of
Mental Disorders (DSM-IV) of the American Psychiatric Association
provides a diagnostic tool for the identification of the disorders
described herein. The person skilled in the art will recognize that
alternative nomenclatures, nosologies, and classification systems
for neurological and psychiatric disorders described herein exist,
and that these evolve with medical and scientific progresses.
A skilled person will be familiar with alternative nomenclatures,
nosologies, and classification systems for the diseases or
conditions referred to herein. For example, the "American
Psychiatric Association: Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition. Arlington, Va., American
Psychiatric Association, 2013" (DSM-5.TM.) utilizes terms such as
depressive disorders, in particular, major depressive disorder,
persistent depressive disorder (dysthymia),
substance-medication-induced depressive disorder; neurocognitive
disorders (NCDs) (both major and mild), in particular,
neurocognitive disorders due to Alzheimer's disease, vascular NCD
(such as vascular NCD present with multiple infarctions), NCD due
to HIV infection, NCD due to traumatic brain injury (TBI), NCD due
to Parkinson's disease, NCD due to Huntington's disease,
frontotemporal NCD, NCD due to prion disease, and
substance/medication-induced NCD; neurodevelopmental disorders, in
particular, intellectual disability, specific learning disorder,
neurodevelopmental motor disorder, communication disorder, and
attention-deficit/hyperactivity disorder (ADHD); substance-related
disorders and addictive disorders, in particular, alcohol use
disorder, amphetamine use disorder, cannabis use disorder, cocaine
use disorder, other hallucinogen use disorder, tobacco use
disorder, opioid use disorder, and phencyclidine use disorder;
schizophrenia spectrum and other psychotic disorders, in
particular, schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic
disorder, substance/medication-induced psychotic disorder; somatic
symptom disorders; hypersomnolence disorder; and cyclothymic
disorder (which under DSM-5.TM. falls under the bipolar and related
disorders category). Such terms may be used by the skilled person
as an alternative nomenclature for some of the diseases or
conditions referred to herein. An additional neurodevelopmental
disorder includes autism spectrum disorder (ASD), which encompasses
according to the DSM-5.TM., disorders previously known by the terms
early infantile autism, childhood autism, Kanner's autism,
high-functioning autism, atypical autism, pervasive developmental
disorder not otherwise specified, childhood disintegrative
disorder, and Asperger's disorder. In particular, the disorder is
autism. Specifiers associated with ASD include those where the
individual has a genetic disorder, such as in Rett syndrome or
Fragile X syndrome.
Therefore, the invention also relates to a compound according to
the general Formula (I), or a stereoisomeric form thereof, or an
N-oxide thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, for use in the treatment of any one of the
diseases mentioned hereinbefore.
The invention also relates to a compound according to the general
Formula (I), or a stereoisomeric form thereof, or an N-oxide
thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, for use in treating any one of the diseases
mentioned hereinbefore.
The invention also relates to a compound according to the general
Formula (I), or a stereoisomeric form thereof, or an N-oxide
thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, for the treatment or prevention, in
particular treatment, of any one of the diseases mentioned
hereinbefore.
The invention also relates to the use of a compound according to
the general Formula (I), or a stereoisomeric form thereof, or an
N-oxide thereof, or a pharmaceutically acceptable salt or a solvate
thereof, in particular, a compound of Formula (I) or a
stereoisomeric form thereof, or a pharmaceutically acceptable salt
or a solvate thereof, for the manufacture of a medicament for the
treatment or prevention of any one of the disease conditions
mentioned hereinbefore.
The compounds of the present invention can be administered to
mammals, preferably humans, for the treatment or prevention of any
one of the diseases mentioned hereinbefore.
In view of the utility of the compounds of Formula (I), there is
provided a method of treating warm-blooded animals, including
humans, suffering from any one of the diseases mentioned
hereinbefore, and a method of preventing in warm-blooded animals,
including humans, any one of the diseases mentioned
hereinbefore.
Said methods comprise the administration, i.e. the systemic or
topical administration, preferably oral administration, of a
therapeutically effective amount of a compound of Formula (I), a
stereoisomeric form thereof, or an N-oxide thereof, or a
pharmaceutically acceptable salt or solvate thereof, in particular,
a compound of Formula (I) or a stereoisomeric form thereof, or a
pharmaceutically acceptable salt or a solvate thereof, to
warm-blooded animals, including humans.
Therefore, the invention also relates to a method for the
prevention and/or treatment of any one of the diseases mentioned
hereinbefore comprising administering a therapeutically effective
amount of a compound according to the invention to a subject in
need thereof.
One skilled in the art will recognize that a therapeutically
effective amount of the NAMs of the present invention is the amount
sufficient to modulate the activity of the mGluR2 and that this
amount varies inter alia, depending on the type of disease, the
concentration of the compound in the therapeutic formulation, and
the condition of the patient. Generally, an amount of NAM to be
administered as a therapeutic agent for treating diseases in which
modulation of the mGluR2 is beneficial, such as the disorders
described herein, will be determined on a case by case by an
attending physician.
Generally, a suitable dose is one that results in a concentration
of the NAM at the treatment site in the range of 0.5 nM to 200
.mu.M, and more usually 5 nM to 50 .mu.M. To obtain these treatment
concentrations, a patient in need of treatment likely will be
administered an effective therapeutic daily amount of about 0.01
mg/kg to about 50 mg/kg body weight, preferably from about 0.01
mg/kg to about 25 mg/kg body weight, more preferably from about
0.01 mg/kg to about 10 mg/kg body weight, more preferably from
about 0.01 mg/kg to about 2.5 mg/kg body weight, even more
preferably from about 0.05 mg/kg to about 1 mg/kg body weight, more
preferably from about 0.1 to about 0.5 mg/kg body weight. The
amount of a compound according to the present invention, also
referred to here as the active ingredient, which is required to
achieve a therapeutically effect will, of course vary on
case-by-case basis, vary with the particular compound, the route of
administration, the age and condition of the recipient, and the
particular disorder or disease being treated. A method of treatment
may also include administering the active ingredient on a regimen
of between one and four intakes per day. In these methods of
treatment the compounds according to the invention are preferably
formulated prior to admission. As described herein below, suitable
pharmaceutical formulations are prepared by known procedures using
well known and readily available ingredients.
The compounds of the present invention may be utilized in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of diseases
or conditions for which compounds of Formula (I) or the other drugs
may have utility, where the combination of the drugs together are
safer or more effective than either drug alone. Examples of such
combinations include the compounds of the invention in combination
with antipsychotic(s), NMDA receptor antagonists (e.g. memantine),
NR2B antagonists, acetylcholinesterase inhibitors (e.g. donepezil,
galantamine, physostigmine and rivastigmine) and/or antidepressant
neurotransmitter reuptake inhibitors. Particular combinations
include the compounds of the invention in combination with
antipsychotics, or the compounds of the invention in combination
with memantine and/or NR2B antagonists.
Pharmaceutical Compositions
The present invention also provides compositions for preventing or
treating diseases in which modulation of the mGluR2 receptor is
beneficial, such as the disorders described herein. While it is
possible for the active ingredient to be administered alone, it is
preferable to present it as a pharmaceutical composition.
Accordingly, the present invention also relates to a pharmaceutical
composition comprising a pharmaceutically acceptable carrier or
diluent and, as active ingredient, a therapeutically effective
amount of a compound according to the invention, in particular a
compound according to Formula (I), an N-oxide, a pharmaceutically
acceptable salt thereof, a solvate thereof or a stereochemically
isomeric form thereof, more in particular, a compound according to
Formula (I), a pharmaceutically acceptable salt thereof, a solvate
thereof or a stereochemically isomeric form thereof. The carrier or
diluent must be "acceptable" in the sense of being compatible with
the other ingredients of the composition and not deleterious to the
recipients thereof.
The compounds according to the invention, in particular the
compounds according to Formula (I), the N-oxides thereof, the
pharmaceutically acceptable salts thereof, the solvates and the
stereochemically isomeric forms thereof, more in particular the
compounds according to Formula (I), the pharmaceutically acceptable
salts thereof, the solvates and the stereochemically isomeric forms
thereof, or any subgroup or combination thereof may be formulated
into various pharmaceutical forms for administration purposes. As
appropriate compositions there may be cited all compositions
usually employed for systemically administering drugs.
The pharmaceutical compositions of this invention may be prepared
by any methods well known in the art of pharmacy, for example,
using methods such as those described in Gennaro et al. Remington's
Pharmaceutical Sciences (18.sup.th ed., Mack Publishing Company,
1990, see especially Part 8: Pharmaceutical preparations and their
Manufacture). To prepare the pharmaceutical compositions of this
invention, a therapeutically effective amount of the particular
compound, optionally in salt form, as the active ingredient is
combined in intimate admixture with a pharmaceutically acceptable
carrier or diluent, which carrier or diluent may take a wide
variety of forms depending on the form of preparation desired for
administration. These pharmaceutical compositions are desirable in
unitary dosage form suitable, in particular, for oral, topical,
rectal or percutaneous administration, by parenteral injection or
by inhalation. For example, in preparing the compositions in oral
dosage form, any of the usual pharmaceutical media may be employed
such as, for example, water, glycols, oils, alcohols and the like
in the case of oral liquid preparations such as, for example,
suspensions, syrups, elixirs, emulsions and solutions; or solid
carriers such as, for example, starches, sugars, kaolin, diluents,
lubricants, binders, disintegrating agents and the like in the case
of powders, pills, capsules and tablets. Because of the ease in
administration, oral administration is preferred, and tablets and
capsules represent the most advantageous oral dosage unit forms in
which case solid pharmaceutical carriers are obviously employed.
For parenteral compositions, the carrier will usually comprise
sterile water, at least in large part, though other ingredients,
for example, surfactants, to aid solubility, may be included.
Injectable solutions, for example, may be prepared in which the
carrier comprises saline solution, glucose solution or a mixture of
saline and glucose solution. Injectable suspensions may also be
prepared in which case appropriate liquid carriers, suspending
agents and the like may be employed. Also included are solid form
preparations that are intended to be converted, shortly before use,
to liquid form preparations. In the compositions suitable for
percutaneous administration, the carrier optionally comprises a
penetration enhancing agent and/or a suitable wetting agent,
optionally combined with suitable additives of any nature in minor
proportions, which additives do not introduce a significant
deleterious effect on the skin. Said additives may facilitate the
administration to the skin and/or may be helpful for preparing the
desired compositions. These compositions may be administered in
various ways, e.g., as a transdermal patch, as a spot-on, as an
ointment.
It is especially advantageous to formulate the aforementioned
pharmaceutical compositions in unit dosage form for ease of
administration and uniformity of dosage. Unit dosage form as used
herein refers to physically discrete units suitable as unitary
dosages, each unit containing a predetermined quantity of active
ingredient calculated to produce the desired therapeutic effect in
association with the required pharmaceutical carrier. Examples of
such unit dosage forms are tablets (including scored or coated
tablets), capsules, pills, powder packets, wafers, suppositories,
injectable solutions or suspensions and the like, teaspoonfuls,
tablespoonfuls, and segregated multiples thereof.
Since the compounds according to the invention are orally
administrable compounds, pharmaceutical compositions comprising aid
compounds for oral administration are especially advantageous.
In order to enhance the solubility and/or the stability of the
compounds of Formula (I) in pharmaceutical compositions, it can be
advantageous to employ .alpha.-, .beta.- or .gamma.-cyclodextrins
or their derivatives, in particular hydroxyalkyl substituted
cyclodextrins, e.g. 2-hydroxypropyl-.beta.-cyclodextrin or
sulfobutyl-.beta.-cyclodextrin. Also co-solvents such as alcohols
may improve the solubility and/or the stability of the compounds
according to the invention in pharmaceutical compositions.
The exact dosage and frequency of administration depends on the
particular compound of formula (I) used, the particular condition
being treated, the severity of the condition being treated, the
age, weight, sex, extent of disorder and general physical condition
of the particular patient as well as other medication the
individual may be taking, as is well known to those skilled in the
art. Furthermore, it is evident that said effective daily amount
may be lowered or increased depending on the response of the
treated subject and/or depending on the evaluation of the physician
prescribing the compounds of the instant invention.
Depending on the mode of administration, the pharmaceutical
composition will comprise from 0.05 to 99% by weight, preferably
from 0.1 to 70% by weight, more preferably from 0.1 to 50% by
weight of the active ingredient, and, from 1 to 99.95% by weight,
preferably from 30 to 99.9% by weight, more preferably from 50 to
99.9% by weight of a pharmaceutically acceptable carrier, all
percentages being based on the total weight of the composition.
The amount of a compound of Formula (I) that can be combined with a
carrier material to produce a single dosage form will vary
depending upon the disease treated, the mammalian species, and the
particular mode of administration. However, as a general guide,
suitable unit doses for the compounds of the present invention can,
for example, preferably contain between 0.1 mg to about 1000 mg of
the active compound. A preferred unit dose is between 1 mg to about
500 mg. A more preferred unit dose is between 1 mg to about 300 mg.
Even more preferred unit dose is between 1 mg to about 100 mg. Such
unit doses can be administered more than once a day, for example,
2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day,
so that the total dosage for a 70 kg adult is in the range of 0.001
to about 15 mg per kg weight of subject per administration. A
preferred dosage is 0.01 to about 1.5 mg per kg weight of subject
per administration, and such therapy can extend for a number of
weeks or months, and in some cases, years. It will be understood,
however, that the specific dose level for any particular patient
will depend on a variety of factors including the activity of the
specific compound employed; the age, body weight, general health,
sex and diet of the individual being treated; the time and route of
administration; the rate of excretion; other drugs that have
previously been administered; and the severity of the particular
disease undergoing therapy, as is well understood by those of skill
in the area.
A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to
about 300 mg taken once a day, or, multiple times per day, or one
time-release capsule or tablet taken once a day and containing a
proportionally higher content of active ingredient. The
time-release effect can be obtained by capsule materials that
dissolve at different pH values, by capsules that release slowly by
osmotic pressure, or by any other known means of controlled
release.
It can be necessary to use dosages outside these ranges in some
cases as will be apparent to those skilled in the art. Further, it
is noted that the clinician or treating physician will know how and
when to start, interrupt, adjust, or terminate therapy in
conjunction with individual patient response.
As already mentioned, the invention also relates to a
pharmaceutical composition comprising the compounds according to
the invention and one or more other drugs for use as a medicament
or for use in the treatment, prevention, control, amelioration, or
reduction of risk of diseases or conditions for which compounds of
Formula (I) or the other drugs may have utility. The use of such a
composition for the manufacture of a medicament as well as the use
of such a composition for the manufacture of a medicament in the
treatment, prevention, control, amelioration or reduction of risk
of diseases or conditions for which compounds of Formula (I) or the
other drugs may have utility are also contemplated. The present
invention also relates to a combination of a compound according to
the present invention and an additional drug selected from the
group of antipsychotics; NMDA receptor antagonists (e.g.
memantine); NR2B antagonists; acetylcholinesterase inhibitors (e.g.
donepezil, galantamine, physostigmine and rivastigmine) and/or
antidepressant neurotransmitter reuptake inhibitors. In particular,
the present invention also relates to a combination of a compound
according to the present invention and antipsychotic(s), or to a
combination of a compound according to the present invention and
memantine and/or an NR2B antagonist. The present invention also
relates to such a combination for use as a medicine. The present
invention also relates to a product comprising (a) a compound
according to the present invention, an N-oxide thereof, a
pharmaceutically acceptable salt thereof or a solvate thereof, in
particular, a pharmaceutically acceptable salt thereof or a solvate
thereof, and (b) an additional component selected from
antipsychotics, NMDA receptor antagonists (e.g. memantine), NR2B
antagonists, acetylcholinesterase inhibitors and/or antidepressant
neurotransmitter reuptake inhibitor(s), as a combined preparation
for simultaneous, separate or sequential use in the treatment or
prevention of a condition in a mammal, including a human, the
treatment or prevention of which is affected or facilitated by the
neuromodulatory effect of mGluR2 allosteric modulators, in
particular negative mGluR2 allosteric modulators. More in
particular the additional component (b) is selected from
antipsychotic(s) or memantine and/or an NR2B antagonist. The
different drugs of such a combination or product may be combined in
a single preparation together with pharmaceutically acceptable
carriers or diluents, or they may each be present in a separate
preparation together with pharmaceutically acceptable carriers or
diluents.
The following examples are intended to illustrate but not to limit
the scope of the present invention.
Chemistry
Several methods for preparing the compounds of this invention are
illustrated in the following Examples. Unless otherwise noted, all
starting materials were obtained from commercial suppliers and used
without further purification.
Hereinafter, "DAD" means diode-array detector; "THF" means
tetrahydrofuran; "DIPE" means diisopropylether; "DMF" means
N,N-dimethylformamide; "Et.sub.2O" means diethylether; "EtOAc"
means ethyl acetate; "DCM" means dichloromethane; "DMSO" means
dimethylsulfoxide; "L" means liter; "HPLC" means high performance
liquid chromatography; "mL" or "ml" means milliliter; "NH.sub.4Ac"
means ammonium acetate; "EtOH" means ethanol; "ES" means
electrospray; "iPrOH" means isopropanol; "MeOH" means methanol;
"eq" means equivalent(s); "RP" means Reverse Phase; "rt" means room
temperature; "M.p." means melting point; "min" means minutes; "h"
means hour(s); "s" means second(s); "TOF" means time of flight;
"QTOF" means Quadrupole-Time of Flight; "sat." means saturated;
"sol." means solution; "RT" means residence time; "S-Phos" means
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl.
Microwave assisted reactions were performed in a single-mode
reactor: Initiator.TM. Sixty EXP microwave reactor (Biotage AB), or
in a multimode reactor: MicroSYNTH Labstation (Milestone,
Inc.).
Flow chemistry reactions were performed in a 1 mL Sigma-Aldrich
Starter Kit microreactor, pumping the reagents through it by a dual
CHEMTRIX Labtrix Start syringe pump and using standard Dolomite
PTFE tubing and ETFE connectors. For further information about this
equipment visit the web:
http://www.chemtrix.com/products/Labtrix-Start-1 for the pumps,
http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotl-
ights/microreactor-explorer-kit.html for the microreactors and
http://www.upchurch.com/ for tubing and connectors. Alternatively,
LTF microreactors can be used. For further information visit the
web: http://www.ltf-gmbh.com/.
Thin layer chromatography (TLC) was carried out on silica gel 60
F254 plates (Merck) using reagent grade solvents. Open column
chromatography was performed on silica gel, particle size 60 .ANG.,
mesh=230-400 (Merck) using standard techniques. Automated flash
column chromatography was performed using ready-to-connect
cartridges from different vendors, on irregular silica gel,
particle size 15-40 .mu.m (normal phase disposable flash columns)
on different flash systems: either a SPOT or LAFLASH systems from
Armen Instrument, or PuriFlash.RTM. 430evo systems from Interchim,
or 971-FP systems from Agilent, or Isolera 1SV systems from
Biotage.
Nuclear Magnetic Resonance (NMR): For a number of compounds,
.sup.1H NMR spectra were recorded either on a Bruker Avance III, on
a Bruker DPX-400 or on a Bruker AV-500 spectrometer with standard
pulse sequences, operating at 400 MHz and 500 MHz, respectively.
Chemical shifts (.delta. are reported in parts per million (ppm)
downfield from tetramethylsilane (TMS), which was used as internal
standard.
Synthesis of Intermediate Compounds
Intermediate 1 (I-1)
##STR00018##
Di-tert-butyl azodicarboxylate (765 g, 3.32 mol) was added to a
stirred solution of ethyl 1H-pyrazole-5-carboxylate (310 g, 2.21
mol), (2R-hydroxy-propyl)-carbamic acid tert-butyl ester (582 g,
3.32 mol) and triphenylphosphine (870 g, 3.31 mol) in THF (4 L)
under nitrogen. The mixture was stirred at rt for 24 h. The solvent
was evaporated in vacuo to yield I-1 (2000 g, 91%), which was used
in the following step without further purification.
Intermediate 2 (I-2)
##STR00019##
Intermediate I-1 (2000 g, 2.02 mol) was dissolved in 4M solution of
HCl in 1,4-dioxane (5 L). The mixture was stirred at 80.degree. C.
for 18 h. The solvent was evaporated in vacuo to yield I-2 (1500 g,
23% purity, 87%), that was used in the following step without
further purification.
Intermediate 3 (I-3)
##STR00020##
I-2 as HCl salt (1500 g, 1.48 mol) was dissolved in a sat. sol. of
NaHCO.sub.3 (4 L). The mixture was stirred at rt for 24 h. The
mixture was filtered and the filtrate was extracted with DCM. The
organic layers were separated, dried (Na.sub.2SO.sub.4), filtered
and the solvents evaporated in vacuo. Then the residue was
crystallized from DCM to yield I-3 (92 g, 76% purity, 96%), which
was used in the following step without further purification.
Intermediate 4 (I-4)
##STR00021##
A mixture of I-3 (5 g, 33.01 mmol), copper (I) iodide (3.78 g,
19.85 mmol) and K.sub.2CO.sub.3 (9.14 g, 66.15 mmol) in toluene
(150 mL) was nitrogen flushed for a few min. Then
4-bromobenzotrifluoride (9.3 mL, 66.1 mmol) and
N,N'-dimethylethylenediamine (2.1 mL, 19.8 mmol) were added. The
mixture was stirred under nitrogen at rt for 10 min and then
stirred at 100.degree. C. for 16 h. Then DMF (20 mL) was added and
the mixture was stirred at 100.degree. C. for 8 h. Then water, a
conc. sol. of ammonia and DCM were added. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; EtOAc in DCM 0/100 to 50/50). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-4 (9.6 g, 98%) as a pale yellow oil.
Intermediates I-5 to I-9
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for intermediate 4.
TABLE-US-00001 Intermediate Starting materials ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031##
Intermediate 10 (I-10)
##STR00032##
Bis(2-methoxyethyl)amino-sulfur trifluoride (1.83 mL, 9.92 mmol)
was added to a stirred solution of I-5 (646 mg, 1.98 mmol) in DCM
(12.5 mL) at 0.degree. C. and under nitrogen. The mixture was left
to warm up to rt and stirred for 3 days. Then was treated with sat.
NaHCO.sub.3 at 0.degree. C. and extracted with EtOAc. The organic
layer was separated, dried (Na.sub.2SO.sub.4), filtered and the
solvents concentrated in vacuo. The crude product was purified by
flash column chromatography (silica; EtOAc in DCM 0/100 to 80/20).
The desired fractions were collected and the solvents concentrated
in vacuo to yield I-10 (345 mg, 53%) as colourless oil that
solidified upon standing.
Intermediate 11 (I-11)
##STR00033##
Iodine (11.55 g, 45.5 mmol) was added to a solution of I-4 (19.2 g,
65.0 mmol) and ammonium cerium(IV) nitrate (24.95 g, 45.5 mmol) in
acetonitrile (350 mL). The mixture was stirred at 70.degree. C. for
1 h. Then the mixture was diluted with EtOAc and washed with a sat.
sol. of Na.sub.2S.sub.2O.sub.3 and brine. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The residue was precipitated with DIPE and
then was purified by short column chromatography (silica, DCM) then
by flash column chromatography (silica; DCM in heptane 50/50 to
100/0). The desired fractions were collected and the solvents
evaporated in vacuo to yield I-11 (24.8 g, 90%) as a solid.
Intermediates I-12 to I-16
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for I-16 (SM means
starting material).
TABLE-US-00002 Intermediate SM ##STR00034## I-5 ##STR00035## I-6
##STR00036## I-7 ##STR00037## I-8 ##STR00038## I-9
Intermediate 17a (I-17a)
##STR00039##
Isopropylmagnesium chloride lithium chloride complex (1.3M
solution, 32.9 mL, 42.7 mmol) was added dropwise to a stirred
solution of I-11 (10 g, 23.7 mmol) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.7 mL, 47.5
mmol) in anhydrous THF (100 mL) at -25.degree. C. under nitrogen
atmosphere. The mixture was stirred for 30 min at -25.degree. C.
Then the reaction was quenched with a 10% NH.sub.4Cl aq sol. and
extracted with EtOAc. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; MeOH in DCM 0/100 to 3/97). The desired fractions were
collected and the solvents evaporated in vacuo. The crude product
was triturated with DIPE, filtered and dried to yield I-17a (6.4 g,
64%) as a white solid. The solution and impure fractions from the
column purification were combined and repurified by flash column
chromatography (silica, EtOAc in Heptane 30/70 to 70/30). The
desired fractions were collected and the solvents evaporated in
vacuo. The product was triturated with DIPE/Heptane, filtered and
dried to yield I-17a (1 g, 10%) as a white solid.
Intermediate 17b (I-17b)
##STR00040##
Isopropylmagnesium chloride lithium chloride complex (1.3M
solution, 273 mL, 354.9 mmol) was added dropwise to a stirred
solution of I-11 (100 g, 237.4 mmol) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20 mL, 95
mmol) in anhydrous THF (1 L) at -25.degree. C. under nitrogen
atmosphere. The mixture was stirred for 30 min at -10.degree. C.
Then the reaction was quenched with sat. sol. NH.sub.4Cl and
extracted with EtOAc. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography to
yield I-17b (43 g, 51%).
Intermediates I-18 to I-22
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for intermediate I-17 (SM
means starting material).
TABLE-US-00003 Intermediate SM ##STR00041## I-12 ##STR00042## I-13
##STR00043## I-14 ##STR00044## I-15 ##STR00045## I-16
Intermediate 20a (I-20a)
##STR00046##
Two solutions of I-11 (3 g, 6.58 mmol) and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.69 mL,
13.16 mmol) in THF (64.5 mL) and isopropylmagnesium chloride
lithium chloride complex (1.3M solution, 7.59 mL, 9.87 mmol) in THF
(30 mL) were pumped through a LTF mixer (0.5 mL/min), at 0.degree.
C., Rt=1 min. The outlet solution was diluted with a sat. sol.
NH.sub.4Cl and extracted with EtOAc. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was triturated with
DIPE/heptane, filtered and dried to yield I-17a (1.772 g, 59%) as a
white solid. The filtrate was evaporated in vacuo and the residue
was purified by flash column chromatography (silica; EtOAc in DCM
0/100 to 100/0). The desired fractions were collected and the
solvents concentrated in vacuo. The residue was triturated with
DIPE, filtered and dried to yield other fraction of I-17a (0.406 g,
13%) as a white solid. The filtrate was evaporated in vacuo and the
residue was triturated again with DIPE/Heptane, filtered and dried
to yield another fraction of I-17a (0.238 g, 8%) as a white
solid.
Intermediate 23 (I-23)
##STR00047##
4,5-Diiodo-2-phenyl-1H-imidazole (0.59 g, 1.49 mmol) was added to a
suspension of sodium sulfite (1.31 g, 10.43 mmol) in water (10 mL)
and EtOH (2.85 mL). The mixture was stirred at refluxed for 18 h.
The solid was filtered and washed with H.sub.2O. The solid was
dried in vacuo to yield I-23 (350 mg, 87%) as a beige solid.
Intermediate 24 (I-24)
##STR00048##
Cyclopropanecarboxaldehyde (0.6 mL, 8.03 mmol) in EtOH (4 mL) was
treated with aqueous ammonia (28% in water, 4 mL) at 55.degree. C.
for 30 min. Pyruvic aldehyde (1.56 mL, 10.12 mmol) was added
dropwise and the mixture was stirred at 60.degree. C. for 16 h. The
solvent was evaporated in vacuo. The mixture was treated with brine
and extracted with EtOAc. The organic layer was separated, dried
(MgSO.sub.4), filtered and the solvent evaporated in vacuo to yield
I-24 (900 mg, 92%).
Intermediate 25 (I-25)
##STR00049##
N-iodosuccinimide (1.62 g, 7.20 mmol) was added portionwise to a
stirred solution of intermediate I-24 (800 mg, 6.54 mmol) in
acetonitrile (38 mL) and the mixture was stirred at rt for 70 min.
The mixture was treated with sat. sol. Na.sub.2S.sub.2O.sub.4 and
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered and the solvents evaporated in vacuo. The
crude product was purified by flash column chromatography (silica,
EtOAc in DCM 0/100 to 30/70). The desired fractions were collected
and the solvents concentrated in vacuo to yield I-25 (1.345 g, 83%)
as a solid.
Intermediate 26 (I-26)
##STR00050##
Lithium diisopropylamide (2.38 mL, 4.77 mmol) was added dropwise to
a solution of
2-[(4-iodoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (1.29 g,
3.97 mmol) in dry THF (29.5 mL) under nitrogen at -78.degree. C.
The mixture was stirred at -78.degree. C. for 10 min and then DMF
(2.21 mL; 28.54 mmol) was added. The mixture was stirred at
-78.degree. C. for 30 min and then warmed to 0.degree. C. for 2 h.
Water was added carefully to the mixture and it was extracted with
EtOAc. The organic layer was washed with brine. The organic layer
was dried (MgSO.sub.4), filtered and the solvents evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; EtOAc in Heptane 0/100 to 10/90). The
desired fractions were collected and the solvents concentrated in
vacuo to yield I-26 (856 mg, 61%) as a white solid.
Intermediate 27 (I-27)
##STR00051##
Sodium carbonate (257 mg, 2.43 mmol) was added to a solution of
I-26 (856 mg, 2.43 mmol) and hydroxylamine hydrochloride (338 mg,
4.86 mmol) in water (4.86 mL). The mixture was stirred at
70.degree. C. for 1 h. After cooling, a precipitate was formed,
filtered, washed with water and dried in vacuo to yield I-27 (884
mg, 99%) as a white solid.
Intermediate 28 (I-28)
##STR00052##
I-27 (884 mg, 2.41 mmol) was stirred at 140.degree. C. in acetic
anhydride (8.86 mL) for 6 h. The solvent was evaporated in vacuo.
The residue was taken up in EtOAc and washed with sat. sol.
Na.sub.2CO.sub.3. The organic layer was dried (MgSO.sub.4),
filtered and the solvents evaporated in vacuo. The residue was
stirred in tetrabutylammonium fluoride (1M in THF, 2.65 mL) at
65.degree. C. for 4 h. This mixture was cooled and poured into
EtOAc and a K.sub.2HPO.sub.4--KH.sub.2PO.sub.4 buffer aq. sol. The
organic layer was separated and the water layer was washed once
more with EtOAc. The combined organic layers were dried
(MgSO.sub.4), filtered and the solvents evaporated in vacuo. The
crude product was purified by flash column chromatography (silica;
MeOH in DCM 0/100 to 5/95). The desired fractions were collected
and the solvents concentrated in vacuo to yield I-28 (255 mg, 48%)
as a yellowish solid.
Intermediate 29 (I-29)
##STR00053##
Sodium hydride (160 mg, 4.24 mmol) was added portionwise to a
solution of ethyl
4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxy-
late (988 mg, 2.82 mmol) in EtOH (20 mL) at 0.degree. C. The
reaction was stirred at rt for 16 h. Then, water was added and the
mixture was extracted with DCM. The organic layer was separated,
dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated in
vacuo to yield I-29 (840 mg, 81% purity, 78%) as a colorless oil
which was used in the next reaction step without further
purification.
Intermediate 30 (I-30)
##STR00054##
Sodium borohydride (102 mg, 2.562 mmol) was added portionwise to a
stirred solution of I-29 (820 mg, 2.135 mmol) in THF (10 mL) at
0.degree. C. The mixture was stirred for 10 min at 0.degree. C.
Then iodomethane (145 .mu.L, 2.345 mmol) was added and the mixture
was stirred at rt for 16 h. Then, more iodomethane (27 .mu.L, 0.430
mmol) was added and the mixture was stirred at rt for 4 h. Then,
water was added and the mixture was extracted with EtOAc. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica, EtOAc in DCM 0/100 to 10/90).
The desired fractions were collected and the solvents evaporated in
vacuo to yield I-30 (570 mg, 83%) as a colorless oil.
Intermediate 31 (I-31)
##STR00055##
Sodium hydride (60% in mineral oils, 155 mg, 3.895 mmol) was added
to 2,5-diiodo-4-methyl-1H-imidazole (867 mg, 2.596 mmol) in THF
(8.7 mL) at 0.degree. C. The mixture was stirred at rt for 10 min.
Then 2-(trimethylsilyl)ethoxymethyl chloride (689 .mu.L, 3.895
mmol) was added at 0.degree. C. and the mixture was stirred for 2
h. The reaction was diluted with NH.sub.4Cl and extracted with
EtOAc. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvents evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; EtOAc in
Heptane 0/100 to 15/85). The desired fractions were collected and
the solvents evaporated in vacuo to yield I-31 (823 mg, 68%) as a
solid.
Intermediate I-81
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for I-31.
TABLE-US-00004 Intermediate Starting material ##STR00056## CAS:
1067894-54-5
Intermediate 32 (I-32)
##STR00057##
N-iodosuccinimide (2.48 g, 11.056 mmol) was added portionwise to a
stirred solution of 2-(4-methyl-1h-imidazol-2-yl)-pyridine (1.6 g,
11.056 mmol) in acetonitrile (58 mL) and the mixture was stirred at
rt for 70 min. The mixture was treated with sat. sol.
Na.sub.2CO.sub.3 and extracted with DCM. The organic layer was
separated, dried (MgSO.sub.4), filtered and the solvents evaporated
in vacuo. The crude product was purified by flash column
chromatography (silica, EtOAc in DCM 0/100 to 30/70). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-32 (1.55 g, 54%) as a solid.
Intermediate I-82
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for I-32.
TABLE-US-00005 Intermediate Starting material ##STR00058## CAS:
119165-68-3
Intermediate 33 (I-33)
##STR00059##
A solution of iodine (6.99 g, 27.555 mmol) in DCM (29 mL) was added
dropwise to a suspension of 2-(1H-imidazol-2-yl)pyridine (2 g,
13.777 mmol) in NaOH (2M in water, 29 mL). The biphasic mixture was
stirred vigorously at rt for 18 h. The aqueous layer was separated
and neutralized with AcOH and then washed with sat. sol.
Na.sub.2S.sub.2O.sub.3 was added until the solution remained
colorless. The suspension was stirred for 10 min and the
precipitate was filtered and dried in vacuo to yield I-33 (4.45 g,
81%) as a solid.
Intermediate I-34
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for I-33
TABLE-US-00006 Intermediate Starting material ##STR00060##
##STR00061##
Intermediate 35 (I-35)
##STR00062##
Sodium sulfite (4.89 g, 38.79 mmol) was added to a suspension of
I-33 (4.4 g, 11.08 mmol) in water (177 mL) and EtOH (90 mL). The
mixture was stirred at reflux for 18 h. The solvents were partially
evaporated in vacuo and the solid was filtered off and washed with
water. The solid was dried in vacuo to yield I-35 (2.5 g, 83%) as a
beige solid.
Intermediate I-83
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for I-35.
TABLE-US-00007 Intermediate Starting material ##STR00063## I-82
Intermediate I-36
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for I-35
TABLE-US-00008 Intermediate Starting material ##STR00064##
##STR00065##
Intermediates I-37 to I-39 and I-84
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for I-31 (SM means
starting material).
TABLE-US-00009 Intermediate SM ##STR00066## I-32 ##STR00067##
##STR00068## I-36 ##STR00069## I-35 ##STR00070## I-83
Intermediate 40 (I-40)
##STR00071##
Pd(PPh.sub.3).sub.4 (199 mg, 0.172 mmol) was added to a stirred
suspension of
2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(759 mg, 3.45 mmol) and
trimethyl-[2-[(2,4,5-tribromoimidazol-1-yl)methoxy]ethyl]silane
(1.5 g, 3.45 mmol) in 1,4-dioxane (15 mL) and sat. sol.
Na.sub.2CO.sub.3 (5 mL). The mixture was stirred at 80.degree. C.
for 16 h. Then the mixture was diluted with water and extracted
with DCM. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvent evaporated in vacuo. The crude product was
purified again by flash column chromatography (silica; EtOAc in DCM
0/100 to 85/15). The desired fractions were collected and the
solvents evaporated in vacuo to yield I-40 (1.1 g, 71%) as an oil
which solidified upon standing.
Intermediates I-41 to I-42
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for I-40.
TABLE-US-00010 Intermediate Starting materials ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077##
Intermediate 43 (I-43)
##STR00078##
n-BuLi (1.6 M in hexanes, 2.1 mL, 3.346 mmol) was added to a
solution of I-40 (1 g, 2.231 mmol) in THF (15 mL) under nitrogen at
-78.degree. C. and the mixture was stirred at the same temperature
for 30 min. Then water was added at -78.degree. C. and the mixture
was allowed to warm to rt and stirred for 1 h more. Then, the
mixture was diluted with sat. sol. NH.sub.4Cl and extracted with
DCM. The organic layer was separated, dried (MgSO.sub.4), filtered
and the solvent evaporated in vacuo. The crude product was purified
by flash chromatography (silica; MeOH in DCM 0/100 to 10/90). The
desired fractions were collected and the solvents concentrated in
vacuo to yield I-43 (500 mg, 60%).
Intermediate 44 (I-44)
##STR00079##
Ethyl
4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxy-
late (1.5 g, 4.29 mmol) was dissolved in 7M ammonia in MeOH (17.5
mL) and the mixture was stirred at 70.degree. C. for 16 h in a
sealed tube. The solvent was evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; MeOH in DCM
0/100 to 10/90). The desired fractions were collected and the
solvents evaporated in vacuo. to yield I-44 (705 mg, 51%).
Intermediate 45 (I-45)
##STR00080##
Lithium bis(trimethylsilyl)amide (4.23 mL, 4.23 mmol) was added to
a stirred solution of ethyl
4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate
(591 mg, 1.692 mmol) and methylamine (33% solution in EtOH, 318
.mu.L, 2.538 mmol) in THF (5.7 mL) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 1 h. The mixture was quenched with sat.
sol. NH.sub.4Cl at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents concentrated in vacuo. The crude product was purified
by flash column chromatography (silica; 7M ammonia in MeOH in DCM
0/100 to 10/90). The desired fractions were collected and the
solvents evaporated in vacuo. to yield I-45 (380 mg, 64%).
Intermediate 46 (I-46)
##STR00081##
Pd(PPh.sub.3).sub.4 (23 mg, 0.020 mmol) was added to a stirred
suspension of I-19 (189 mg, 0.446 mmol) and I-43 (150 mg, 0.406
mmol) in 1,4-dioxane (3 mL) and sat. sol. Na.sub.2CO.sub.3 (1 mL).
The mixture was stirred at 90.degree. C. for 16 h. Then the mixture
was diluted with H.sub.2O and extracted with DCM. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and the solvent
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-46 (220 mg, 93%) as an oil.
Intermediates I-47 to I-63
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for intermediate
I-46.
TABLE-US-00011 Reagents Intermediate ##STR00082## ##STR00083##
I-17b ##STR00084## ##STR00085## I-17b ##STR00086## ##STR00087##
I-17b ##STR00088## ##STR00089## I-17b ##STR00090## ##STR00091##
I-17b ##STR00092## ##STR00093## I-17b ##STR00094## ##STR00095##
I-19 ##STR00096## ##STR00097## I-22 ##STR00098## ##STR00099## I-22
##STR00100## ##STR00101## I-20b ##STR00102## ##STR00103## I-20a
##STR00104## ##STR00105## I-20a ##STR00106## ##STR00107## I-20a
##STR00108## ##STR00109## I-20b ##STR00110## ##STR00111## I-20a
Mixture of I-37a and I-37b ##STR00112## I-20a ##STR00113##
##STR00114## I-20a I-84 ##STR00115## I-20a I-85 ##STR00116##
I-20a
Intermediate 64 (I-64)
##STR00117##
Sodium hydride (60% in mineral oils, 6 mg, 0.291 mmol) was added to
I-60 (100 mg, 0.171 mmol) in THF (0.3 mL) at 0.degree. C. The
mixture was stirred at 0.degree. C. for 40 min. Then iodomethane
(18 .mu.L, 0.291 mmol) was added at 0.degree. C. and the mixture
was stirred at 0.degree. C. for 10 min and at rt for 2.5 h. The
reaction was diluted with water and extracted with EtOAc. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; MeOH in DCM 0/100 to 10/90).
The desired fractions were collected and the solvents evaporated in
vacuo to yield I-64 (50 mg, 48%).
Intermediate 65 (I-65)
##STR00118##
To a mixture of 2,4-dimethylimidazole (200 mg, 2.080 mmol) in
acetonitrile (6 mL) at 0.degree. C. was added N-bromosuccinimide
(444 mg, 2.496 mmol) portionwise. Then the mixture was left
stirring at rt for 1 h. Then water, diluted sol. Na.sub.2CO.sub.3
and diluted sol. Na.sub.2S.sub.2O.sub.3 were added and extracted
with DCM. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvents evaporated in vacuo.
The crude product was purified by flash column chromatography
(silica; 7N ammonia in MeOH in DCM 0/100 to 3/97). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-65 (210 mg, 58%) as a white solid.
Intermediate 66 (I-66)
##STR00119##
2-Methylimidazole (821 mg, 10 mmol) was added portionwise to a
stirred suspension of sodium hydride (60% in mineral oils, 440 mg,
11 mmol) in THF (50 mL) at 0.degree. C. The mixture was stirred at
rt for 30 min. Then benzyl chloromethyl ether (1.39 mL, 10 mmol)
was added and the mixture was stirred at rt for 16 h. The mixture
was treated with water and extracted with EtOAc. The organic layer
was separated, dried (MgSO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica, 7 N solution of ammonia in MeOH in DCM
0/100 to 5/95). The desired fractions were collected and the
solvents evaporated in vacuo to yield I-66 (1.68 g, 83%) as a
colorless oil.
The following intermediates were synthesized by following an
analogous synthetic procedure as reported for intermediate
I-66.
TABLE-US-00012 Intermediate Starting material ##STR00120##
##STR00121##
Intermediate 68 (I-68)
##STR00122##
Lithium diisopropylamide (993 .mu.L, 1.986 mmol) was added dropwise
to a solution of I-67 (520 mg, 1.655 mmol) in dry THF (10 mL) under
nitrogen at -78.degree. C. The mixture was stirred at -78.degree.
C. for 10 min then DMF (640 .mu.L, 8.277 mmol) was added. The
mixture was stirred at -78.degree. C. for 1 h and then left to rt
for 18 h. Water was added carefully and it was extracted with
EtOAc. The organic layer was dried (MgSO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; MeOH in DCM 0/100 to 03/97).
The desired fractions were collected and the solvents evaporated in
vacuo to yield I-68 (267 mg, 47%) as a solid.
Intermediate 69 (I-69)
##STR00123##
Sodium carbonate (165 mg, 1.56 mmol) was added to a solution of
I-68 (267 mg, 0.780 mmol) and hydroxylamine hydrochloride (108 mg,
1.56 mmol) in water (3.1 mL). The mixture was stirred at 70.degree.
C. for 90 min and a precipitate was formed. After cooling to rt,
the suspension was filtered, washed with water and dried in vacuo
to yield I-69 (295 mg, quant.) as a white solid.
Intermediate 70 (I-70)
##STR00124##
I-69 (278 mg, 0.778 mmol) in acetic anhydride (3 mL) was stirred at
140.degree. C. for 20 h.
The solvent was evaporated in vacuo. The residue was diluted with
EtOAc and washed with sat. sol. Na.sub.2CO.sub.3. The organic layer
was dried (MgSO.sub.4), filtered and the solvents evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; MeOH in DCM 0/100 to 02/98). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-70 (280 mg, quant.).
Intermediate 71 (I-71)
##STR00125##
Diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (626
mg, 1.549 mmol) was added to a solution of 1-benzyl-2-iodoimidazole
(220 mg, 0.774 mmol) and copper (147 mg, 2.323 mmol) in anhydrous
DMF (3 mL). The mixture was stirred at 65.degree. C. for 2.5 h. The
mixture was diluted with water, quenched with aq. sol. NH.sub.3 and
extracted with DCM. The organic layer was dried (MgSO.sub.4),
filtered and the solvents evaporated in vacuo. The crude product
was purified by flash column chromatography (silica; eluent DCM
100%). The desired fractions were collected and the solvents
evaporated in vacuo to yield I-71 (65 mg, 37%) as an oil.
Intermediate 72 (I-72)
##STR00126##
Palladium(II) acetate (5 mg, 0.022 mmol) and
butyldi-1-adamantylphosphine (12 mg, 0.033 mmol) were added to a
stirred mixture of I-66 (200 mg, 0.448 mmol), I-15 (109 mg, 0.538
mmol) and K.sub.2CO.sub.3 (124 mg, 0.896 mmoL) in DMF (4 mL)
(previously flushed with nitrogen for 5 min) in a sealed tube. The
mixture was stirred at 120.degree. C. for 30 h. The mixture was
diluted with water and extracted with EtOAc. The organic layer was
dried, filtered and the solvents evaporated in vacuo. The crude
product was purified by flash column chromatography (silica; MeOH
in DCM 0/100 to 03/97). The desired fractions were collected and
the solvents evaporated in vacuo to yield I-72 (110 mg, 47%).
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for intermediate
I-72.
TABLE-US-00013 Reagents Intermediate I-71 I-11 ##STR00127##
The following intermediate was synthesized by following an
analogous synthetic procedure as reported for intermediate
I-46.
TABLE-US-00014 Reagents Intermediate I-70 I-20b ##STR00128##
Intermediate 75 (I-75)
##STR00129##
Bis(triphenylphosphine)palladium(II) chloride (0.25 g, 0.356 mmol)
was added to a stirred suspension of I-11 (3 g, 7.12 mmol),
tributyl-(1-ethoxyvinyl)tin (2.88 g, 8.548 mmol) and
K.sub.2CO.sub.3 (1.969 g, 14.245 mmol) in a degassed mixture of
1,4-dioxane (30 mL) and water (6 mL) in a sealed tube and under
nitrogen. The mixture was stirred at 110.degree. C. for 20 h. Then
the mixture was treated with sol. HCl (2M in H.sub.2O, 17.8 mL,
35.6 mmol) and the mixture was stirred at 80.degree. C. for 1 h.
Then the mixture was basified with sol. NaOH (2M in H.sub.2O) at
0.degree. C. and extracted with EtOAc. The organic phase was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvent
evaporated in vacuo. The crude compound was purified by flash
column chromatography (silica, EtOAc in DCM 0/100 to 30/70). The
desired fractions were collected and the solvent evaporated in
vacuo to yield I-75 (1.84 g, 76%) as a pale yellow solid.
Intermediate 76 (I-76)
##STR00130##
I-75 (1.84 g, 5.455 mmol) was added to a stirred solution of
pyridinium tribromide (1.22 g, 3.818 mmol) in DCM (38 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for 20 min and
then at rt for 30 min. The mixture was treated with sol.
Na.sub.2S.sub.2O.sub.3 and extracted with DCM. The organic layer
was separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica; EtOAc in DCM 0/100 to 10/90). The desired
fractions were collected and the solvents evaporated in vacuo to
yield I-76 (850 mg, 37%) as a colourless oil.
Intermediate 77 (I-77)
##STR00131##
Sodium hydride (60% in mineral oils, 468 mg, 11.7 mmol) was added
to 2-chloro-1H-imidazole (800 mg, 7.8 mmol) in THF (24 mL) at
0.degree. C. The mixture was stirred at rt for 10 min. Then
2-(trimethylsilyl)ethoxymethyl chloride (2 mL, 11.7 mmol) was added
at 0.degree. C. and the mixture was stirred for 2 h. The mixture
was diluted with sat. sol. NH.sub.4Cl and extracted with EtOAc. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; EtOAc in Heptane 0/100 to
50/50). The desired fractions were collected and the solvents
concentrated in vacuo to yield I-77 (1.52 g, 89%).
Intermediate 78 (I-78)
##STR00132##
Two solutions of I-77 (328 mg, 1.41 mmol) in THF (1.8 mL) and
2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride
complex (0.9M in THF, 1.77 mL, 1.60 mmol) were pumped through a
Sigma-Aldrich reactor (1 mL volume) at 0.5 ml/min each one (RT=1
min) and at rt. The outlet solution was collected in a sealed vial
under nitrogen atmosphere. To this solution zinc dichloride (0.5M
in THF, 2 mL, 1.03 mmol) was added and the reaction mixture was
stirred at rt for 15 min. Then, Pd(PPh.sub.3).sub.4 (54 mg, 0.047
mmol) and I-11 (400 mg, 0.940 mmol) in THF (1 mL) were added and
the mixture was stirred at 50.degree. C. for 16 h. Then the mixture
was diluted with sat. sol. NH.sub.4Cl and extracted with EtOAc. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvent evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; EtOAc in Heptane 0/100 to
40/60). The desired fractions were collected and the solvents
evaporated in vacuo to yield I-78 (375 mg, 75%) as a white
solid.
Intermediate 79 (I-79)
##STR00133##
Cyclobutyl zinc bromide (0.5M in THF, 0.48 mL, 0.242 mmol) was
added to a suspension of I-78 (85 mg, 0.161 mmol),
Pd.sub.2(dba).sub.3 (7 mg, 0.008 mmol) and S-Phos (6 mg, 0.016
mmol) in THF (0.44 mL) under nitrogen atmosphere. The mixture was
stirred at 60.degree. C. for 3 h. Then, sat. sol. NH.sub.4Cl was
added and the mixture extracted with EtOAc. The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and the solvents
evaporated in vacuo. The crude product was purified by flash column
chromatography (silica, EtOAc in DCM 0:100 to 50:50). The desired
fractions were collected and evaporated in vacuo to yield I-79 (68
mg, 77%) as a yellow oil.
Intermediate 80 (I-80)
##STR00134##
Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol) was added to a stirred
suspension of I-78 (150 mg, 0.285 mmol) and
2-methylpyridine-4-boronic acid pinacol ester (75 mg, 0.342 mmol)
in 1,4-dioxane (2 mL) and sat. sol. Na.sub.2CO.sub.3 (1 mL). The
mixture was stirred at 90.degree. C. for 36 h. Additional
Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol) was added and the mixture
was stirred at 100.degree. C. for 6 h. Then, the mixture was
diluted with EtOAc and filtered through a pad of diatomaceous
earth. The filtrate was evaporated in vacuo. The crude product was
purified by flash column chromatography (silica, EtOAc in DCM 0/100
to 100/0). The desired fractions were collected and the solvents
evaporated in vacuo to yield I-80 (60 mg, 36%) as a yellow oil.
Preparation of Final Compounds
Example 1 (E-1, Co. No. 27)
##STR00135##
Pd(PPh.sub.3).sub.4 (51 mg, 0.044 mmol) was added to a stirred
suspension of I-20a (400 mg, 0.877 mmol) and
4-bromo-2-methyl-1H-imidazole (141 mg, 0.877 mmol) in 1,4-dioxane
(8 mL) and sat. sol. Na.sub.2CO.sub.3 (4 mL). The mixture was
nitrogen flushed and then stirred at 120.degree. C. for 15 min
under microwave irradiation. Then the mixture was diluted with
H.sub.2O and extracted with DCM. The organic layer was separated,
dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated in
vacuo. The crude product was purified by flash column
chromatography (silica; MeOH in EtOAc 0/100 to 2/98). The desired
fractions were collected and the solvents evaporated in vacuo. The
product was triturated with heptane, filtered and dried in vacuo to
yield final compound Co. No. 27 (200 mg, 56%) as a white solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 1.56 (d, J=6.6 Hz,
3 H) 2.29 (s, 2 H) 2.31 (s, 1 H) 3.99-4.13 (m, 1 H) 4.27-4.40 (m, 1
H) 4.68-4.81 (m, 1 H) 7.39 (d, J=1.2 Hz, 0.25 H) 7.61-7.68 (m, 1 H)
7.79 (d, J=2.0 Hz, 0.75 H) 7.88 (d, J=1.7 Hz, 0.75 H) 7.91 (d,
J=1.2 Hz, 0.25 H) 7.94 (d, J=8.7 Hz, 0.75 H) 7.97 (d, J=9.0 Hz,
0.25 H) 7.98 (s, 0.75 H) 8.04 (s, 0.25 H) 11.73 (br. s., 0.75 H)
11.88 (br. s., 0.25 H).
Following a procedure analogous to that described for E-1, the
following compounds were also synthesized:
TABLE-US-00015 Intermediate Reagent Final Compound I-17a
##STR00136## ##STR00137## I-17a ##STR00138## ##STR00139## I-17b
##STR00140## ##STR00141## I-17a ##STR00142## ##STR00143## I-17b
##STR00144## ##STR00145## I-17a ##STR00146## ##STR00147## I-17a
##STR00148## ##STR00149## I-22 ##STR00150## ##STR00151## I-20b
##STR00152## ##STR00153## I-20a ##STR00154## ##STR00155##
I-20a/I-20b ##STR00156## ##STR00157## I-20a ##STR00158##
##STR00159##
Example 2 (E-2, Co. No. 24)
##STR00160##
Pd(PPh.sub.3).sub.4 (46 mg, 0.040 mmol) was added to a deoxygenated
stirred mixture of I-18 (261 mg, 0.576 mmol),
5-bromo-2-methyl-1H-imidazole (463 mg, 2.88 mmol) and
K.sub.2CO.sub.3 (397 mg, 2.88 mmol) in 1,4-dioxane (7 mL) and water
(1.9 mL) in a sealed tube under nitrogen. The mixture was stirred
at 120.degree. C. for 30 min under microwave irradiation. Then the
mixture was diluted with water/brine and extracted with EtOAc. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was triturated
with DCM, filtered and dried in vacuo. The crude product was
purified by flash column chromatography (silica; EtOAc in DCM 0/100
to 100/0 and MeOH in EtOAc 0/100 to 4/96). The desired fractions
were collected and the solvents concentrated in vacuo to yield the
product as a syrup which was triturated with DIPE, filtered and
dried in vacuo to yield Co. No. 24 (116 mg, 49%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.73 (d, J=6.5 Hz, 3
H) 2.42 (s, 3 H) 4.00 (dd, J=12.6, 7.5 Hz, 1 H) 4.26 (dd, J=12.7,
4.2 Hz, 1 H) 4.69-4.80 (m, 1 H) 5.68 (d, J=46.7 Hz, 2 H) 7.30 (d,
J=1.4 Hz, 1 H) 7.50 (dd, J=8.4, 0.8 Hz, 1 H) 7.69 (s, 1 H) 7.81 (d,
J=8.6 Hz, 1 H) 7.90 (s, 1 H) 11.85 (br. s., 1 H).
Example 3 (E-3, Co. No. 19)
##STR00161##
A solution of I-46 (220 mg, 0.376 mmol) in HCl (6 M in iPrOH, 6.3
mL) was stirred at 60.degree. C. for 16 h. Then the solvent was
concentrated in vacuo. The mixture was diluted with sat. sol.
Na.sub.2CO.sub.3 and extracted with DCM. The organic layer was
separated, dried (MgSO.sub.4), filtered and the solvents
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica; MeOH in DCM 0/100 to 10/90). The
desired fractions were collected and the solvents evaporated in
vacuo. The product was triturated with Et.sub.2O, filtered and
dried in vacuo to give a solid that was triturated with DCM,
filtered and dried in vacuo to yield Co. No. 19 (125 mg, 73%) as a
solid as a solid (mixture of tautomers 90:10). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.72 (d, J=6.7 Hz, 3 H) 3.94 (dd,
J=12.7, 7.4 Hz, 1 H) 4.21 (dd, J=12.7, 4.2 Hz, 1 H) 4.57 (s, 2 H)
4.68-4.81 (m, 1 H) 6.54 (d, J=8.6 Hz, 1 H) 7.28 (dd, J=8.6, 2.5 Hz,
1 H) 7.47 (d, J=1.2 Hz, 1 H) 7.52 (d, J=2.5 Hz, 1 H) 7.58 (d, J=8.6
Hz, 1 H) 7.93 (dd, J=8.6, 2.5 Hz, 1 H) 7.94 (s, 1 H) 8.64 (d, J=1.8
Hz, 1 H) 12.70 (br. s., 0.9 H) 12.79 (br. s., 0.1 H).
Following a procedure analogous to that described for E-3, the
following compounds were also synthesized (in the table below, I
means intermediate):
TABLE-US-00016 I Final Compound I-47 ##STR00162## I-48 ##STR00163##
I-49 ##STR00164## I-50 ##STR00165## I-51 ##STR00166## I-52
##STR00167## I-53 ##STR00168## I-54 ##STR00169## I-55 ##STR00170##
I-56 ##STR00171## I-57 ##STR00172## I-58 ##STR00173## I-59
##STR00174## I-60 ##STR00175## I-64 ##STR00176## I-61 ##STR00177##
I-62 ##STR00178## I-63 ##STR00179## I-79 ##STR00180## I-80
##STR00181## I-86 ##STR00182## I-86 ##STR00183## I-87
##STR00184##
Example 4 (E-4, Co. No. 23)
##STR00185##
Boron tribromide (1M in DCM, 605 .mu.L, 0.605 mmoL) was added to a
suspension of I-72 (105 mg, 0.202 mmol) in toluene (2 mL) under
nitrogen. The mixture was stirred at 90.degree. C. for 3 h. Then
the mixture was quenched with 10% aq. sol. K.sub.2CO.sub.3 and
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered and the solvents evaporated in vacuo. The
crude product was purified by flash column chromatography (silica;
MeOH in DCM 0/100 to 07/93). The desired fractions were collected
and the solvents evaporated in vacuo. The product was triturated
with DIPE, filtered and dried in vacuo to yield Co. No. 23 (42 mg,
52%) as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.74
(d, J=6.5 Hz, 3 H) 2.45 (s, 3 H) 4.03 (dd, J=12.5, 7.6 Hz, 1 H)
4.27 (dd, J=12.5, 4.2 Hz, 1 H) 4.72-4.82 (m, 1 H) 7.33 (br. s., 1
H) 7.77 (dd, J=8.7, 1.5 Hz, 1 H) 7.87-7.94 (m, 2 H) 7.95 (d, J=2.1
Hz, 1 H) 11.72 (br. s., 1 H).
Following a procedure analogous to that described for E-4, the
following compounds were also synthesized:
TABLE-US-00017 Intermediate Final Compound I-74 ##STR00186##
Example 5 (E-5, Co. No. 8)
##STR00187##
A solution of I-73 (62 mg, 0.119 mmol) and acetic acid (0.05 mL) in
EtOH (2 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm
Pd(OH).sub.2 20% cartridge, full H.sub.2 mode, 100.degree. C., 3
cycles). The solvent was evaporated in vacuo. The crude product was
purified by flash column chromatography (silica; EtOAc in Heptane
0/100 to 60/40). The desired fractions were collected and the
solvent evaporated in vacuo. The product was purified via RP HPLC
(Stationary phase: C18 Sunfire 30.times.100 mm 5 um, Mobile phase:
Gradient from 80% 10 mM NH.sub.4CO.sub.3H pH 9 solution in Water,
20% CH.sub.3CN to 0% 10 mM NH.sub.4CO.sub.3H pH 9 solution in
Water, 100% CH.sub.3CN) to yield Co. No. 8 (5 mg, 10%) as a solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.75 (d, J=6.4 Hz, 3
H) 4.02 (dd, J=12.7, 7.5 Hz, 1 H) 4.29 (dd, J=12.7, 4.0 Hz, 1 H)
4.75-4.83 (m, 1 H) 7.48 (s, 1 H) 7.54 (d, J=8.4 Hz, 2 H) 7.78 (d,
J=8.7 Hz, 2 H) 7.98 (s, 1 H) 13.15 (br. s., 1 H).
Example 6 (E-6, Co. No. 1)
##STR00188##
N-bromosuccinimide (386 mg, 2.167 mmol) was added to a stirred
solution of Co. No. 12 (712 mg, 1.9705 mmol) in acetonitrile (3.6
mL) at 0.degree. C. The mixture was stirred at rt for 1 h. The
mixture was treated with sat. sol. NaHCO.sub.3 and extracted with
EtOAc. The organic layer was dried (Na.sub.2SO.sub.4), filtered and
the solvents evaporated in vacuo. The crude product was purified by
flash column chromatography (silica; EtOAc in DCM 0/100 to 50/50).
The desired fractions were collected and the solvents evaporated in
vacuo to yield Co. No. 1 (580 mg, 67%) as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.75 (d, J=6.4 Hz, 3 H) 4.01
(dd, J=12.7, 7.5 Hz, 1 H) 4.29 (dd, J=12.9, 4.2 Hz, 1 H) 4.76-4.84
(m, 1 H) 7.47 (d, J=1.2 Hz, 1 H) 7.52 (d, J=8.4 Hz, 2 H) 7.78 (d,
J=8.4 Hz, 2 H) 8.63 (s, 1 H) 12.98 (br. s., 1 H).
Following a procedure analogous to that described for E-6, the
following compounds were also synthesized:
TABLE-US-00018 Intermediate Final Compound Co. No. 11 and
N-chlorosuccinimide ##STR00189##
Example 7 (E-7, Co. No. 15)
##STR00190##
A mixture of I-76 (220 mg, 0.528 mmol), 2-methylaminopyrimidine (58
mg, 0.528 mmol) and 4-(dimethylamino)pyridine (0.6 mg, 0.005 mmol)
in acetonitrile (2 mL) was stirred at 85.degree. C. for 16 h. Then,
hydrazine hydrate (179 .mu.L, 3.7 mmol) was added and the mixture
was stirred at 100.degree. C. for 10 min under microwave
irradiation. Then, the solvent was evaporated in vacuo and the
crude product was purified by flash column chromatography (silica;
MeOH in DCM 0/100 to 10/90). The desired fractions were collected
and the solvents evaporated in vacuo to yield Co. No. 15 (135 mg,
65%) as a yellow solid. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
ppm 1.70 (d, J=6.4 Hz, 3 H) 2.94 (s, 3 H) 3.96 (dd, J=12.6, 7.4 Hz,
1 H) 4.23 (dd, J=12.6, 4.2 Hz, 1 H) 4.26 (br. s., 1 H) 4.66-4.75
(m, 1 H) 7.07 (s, 1 H) 7.51 (d, J=8.4 Hz, 2 H) 7.75 (d, J=8.4 Hz, 2
H) 7.83 (s, 1 H) 11.10 (br. s., 1 H).
Example 8 (E-8, Co. No. 25)
##STR00191##
Pd(PPh.sub.3).sub.4 (23.2 mg, 20.1 mmol) was added to a stirred
suspension of I-20b (150 mg, -0.40 mmol) and
2-cyclopropyl-5-iodo-1H-imidazole (112.8 mg, 0.48 mmol) in a sat.
sol. of NaHCO.sub.3 (2 mL) and 1,4-dioxane (1 mL). The mixture was
stirred at 120.degree. C. for 10 min under microwave irradiation.
The mixture was concentrated in vacuo. The crude product was
purified by flash column chromatography (silica; MeOH/DCM 0/100 to
6/94). The desired fractions were collected and evaporated in
vacuo. The product was purified by RP HPLC (Stationary phase: C18
XBridge 30.times.100 mm 5 .mu.m; mobile phase: gradient from 60%
0.1% NH.sub.4CO.sub.3H/NH.sub.4OH pH 9 solution in water, 40%
CH.sub.3CN to 43% 0.1% NH.sub.4CO.sub.3H/NH.sub.4OH pH 9 solution
in water, 57% CH.sub.3CN), to yield Co. No. 25 (90 mg, 51%) as a
light yellow fluffy solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.91-1.02 (m, 4 H) 1.72 (d, J=6.7 Hz, 3 H) 1.90-2.00
(m, 1 H) 3.98 (dd, J=12.5, 7.4 Hz, 1 H) 4.24 (dd, J=12.7, 4.2 Hz, 1
H) 4.68-4.79 (m, 1 H) 7.28 (s, 1 H) 7.42 (dd, J=8.3, 1.4 Hz, 1 H)
7.60 (d, J=2.1 Hz, 1 H) 7.82 (d, J=8.6 Hz, 1 H) 7.88 (s, 1 H) 11.88
(br s, 1 H).
TABLE-US-00019 TABLE 1 The following compounds were prepared
following the methods exemplified in the Experimental Part (Ex.
No.). Compounds exemplified and described in the experimental part
are marked with an asterisk *. cPr means cyclopropyl, iPr means
isopropyl and cBu means cyclobutyl. ##STR00192## Co. Ex. No. No.
R.sup.1 R.sup.2 R.sup.3 >CR.sup.4R.sup.5 Salt Form 1 E-6*
##STR00193## --H --Br >CH(CH.sub.3) (S) 2 E-1 ##STR00194## --cPr
--H >CH(CH.sub.3) (S) 3 E-6 ##STR00195## ##STR00196## --Cl
>CH(CH.sub.3) (S) 4 E-1 ##STR00197## --CH.sub.3 --H
>CH(CH.sub.3) (S) 5 E-1 ##STR00198## ##STR00199## --H
>CH(CH.sub.3) (S) 6 E-1 ##STR00200## --iPr --H >CH(CH.sub.3)
(S) 7 E-1 ##STR00201## --cPr --CH.sub.3 >CH(CH.sub.3) (S) 8 E-5*
##STR00202## --CF.sub.3 --H >CH(CH.sub.3) (S) 9 E-3 ##STR00203##
##STR00204## --Br >CH(CH.sub.3) (S) 10 E-1 ##STR00205## --CN --H
>CH(CH.sub.3) (S) 11 E-3 ##STR00206## ##STR00207## --H
>CH(CH.sub.3) (S) 12 E-1 ##STR00208## --H --H >CH(CH.sub.3)
(S) 13 E-3 ##STR00209## --CH.sub.2OCH.sub.3 --H >CH(CH.sub.3)
(S) 14 E-3 ##STR00210## ##STR00211## --CH.sub.3 >CH(CH.sub.3)
(S) 15 E-7* ##STR00212## --NHCH.sub.3 --H >CH(CH.sub.3) (S) 16
E-3 ##STR00213## ##STR00214## --CH.sub.3 >CH(CH.sub.3) (S) 17
E-3 ##STR00215## ##STR00216## --CH.sub.3 >CH(CH.sub.3) (S) 18
E-3 ##STR00217## ##STR00218## --H >CH(CH.sub.3) (S) 19 E-3*
##STR00219## ##STR00220## --H >CH(CH.sub.3) (S) 20 E-3
##STR00221## ##STR00222## --H >CH(CH.sub.3) (S) 21 E-1
##STR00223## --cPr --CH.sub.3 >CH(CH.sub.3) (S) 22 E-3
##STR00224## ##STR00225## --H >CH(CH.sub.3) (S) 23 E-4*
##STR00226## --CH.sub.3 --H >CH(CH.sub.3) (S) 24 E-2*
##STR00227## --CH.sub.3 --H >CH(CH.sub.3) (S) 25 E-1
##STR00228## --cPr --H >CH(CH.sub.3) (S) 26 E-1 ##STR00229##
--iPr --H >CH(CH.sub.3) (S) 27 E-1* ##STR00230## --CH.sub.3 --H
>CH(CH.sub.3) (S) 28 E-1 ##STR00231## --cPr --CH.sub.3
>CH(CH.sub.3) (S) 29 E-4 ##STR00232## --CN --H >CH(CH.sub.3)
(S) 30 E-1 ##STR00233## --CH.sub.3 --CH.sub.3 >CH(CH.sub.3) (S)
.cndot.HCl 31 E-3 ##STR00234## --CONH.sub.2 --H >CH(CH.sub.3)
(S) 32 E-3 ##STR00235## ##STR00236## --CH.sub.3 >CH(CH.sub.3)
(S) 33 E-3 ##STR00237## ##STR00238## --H >CH(CH.sub.3) (S) 34
E-3 ##STR00239## ##STR00240## --CH.sub.3 >CH(CH.sub.3) (S) 35
E-3 ##STR00241## --CONHCH.sub.3 --H >CH(CH.sub.3) (S) 36 E-3
##STR00242## --CON(CH.sub.3).sub.2 --H >CH(CH.sub.3) (S) 37 E-3
##STR00243## ##STR00244## --H >CH(CH.sub.3) (S) 38 E-3
##STR00245## ##STR00246## --CH.sub.3 >CH(CH.sub.3) (S) 39 E-3
##STR00247## ##STR00248## --H >CH(CH.sub.3) (S) 40 E-3
##STR00249## --cBu --H >CH(CH.sub.3) (S) 41 E-3 ##STR00250##
##STR00251## --H >CH(CH.sub.3) (S) 42 E-1 ##STR00252##
##STR00253## --H >CH(CH.sub.3) (S) 43 E-3 ##STR00254##
##STR00255## --H >CH(CH.sub.3) (S) 44 E-3 ##STR00256##
##STR00257## --H >CH(CH.sub.3) (S) 45 E-3 ##STR00258##
##STR00259## --CN >CH(CH.sub.3) (S)
Analytical Part Melting Points:
Values are peak values, and are obtained with experimental
uncertainties that are commonly associated with this analytical
method.
DSC823e (A)
For a number of compounds, melting points were determined with a
DSC823e (Mettler-Toledo) apparatus. Melting points were measured
with a temperature gradient of 10.degree. C./minute. Maximum
temperature was 300.degree. C. Values are peak values.
Mettler Toledo Mettler FP 81HT/FP90 Apparatus (B)
For a number of compounds, melting points were determined in open
capillary tubes on a Mettler FP 81HT/FP90 apparatus. Melting points
were measured with a temperature gradient of 1, 3, 5 or 10.degree.
C./minute. Maximum temperature was 300.degree. C. The melting point
was read from a digital display.
LCMS
General Procedure
The High Performance Liquid Chromatography (HPLC) measurement was
performed using a LC pump, a diode-array (DAD) or a UV detector and
a column as specified in the respective methods. If necessary,
additional detectors were included (see table of methods
below).
Flow from the column was brought to the Mass Spectrometer (MS)
which was configured with an atmospheric pressure ion source. It is
within the knowledge of the skilled person to set the tune
parameters (e.g. scanning range, dwell time . . . ) in order to
obtain ions allowing the identification of the compound's nominal
monoisotopic molecular weight (MW) and/or exact mass monoisotopic
molecular weight. Data acquisition was performed with appropriate
software.
Compounds are described by their experimental retention times (Rt)
and ions. If not specified differently in the table of data, the
reported molecular ion corresponds to the [M+H].sup.+ (protonated
molecule) and/or [M-H].sup.- (deprotonated molecule). In case the
compound was not directly ionizable the type of adduct is specified
(i.e. [M+NH.sub.4].sup.+, [M+HCOO].sup.-, [M+CH.sub.3COO].sup.-
etc. . . . ). For molecules with multiple isotopic patterns (Br, Cl
. . . ), the reported value is the one obtained for the lowest
isotope mass. All results were obtained with experimental
uncertainties that are commonly associated with the method
used.
Hereinafter, "SQD" Single Quadrupole Detector, "MSD" Mass Selective
Detector, "QTOF" Quadrupole-Time of Flight, "rt" room temperature,
"BEH" bridged ethylsiloxane/silica hybrid, "CSH" charged surface
hybrid, "UPLC" Ultra Performance Liquid Chromatography, "DAD" Diode
Array Detector.
TABLE-US-00020 TABLE 2 LC-MS Methods (Flow expressed in mL/min;
column temperature (T) in .degree. C.; Run time in min). Flow Run
Method Instrument Column Mobile phase Gradient Col T time 1 Waters:
Waters: A: 95% From 95% A 1 5 Acquity .RTM. CSH .TM. C18
CH.sub.3COONH.sub.4 to 5% A in 50 UPLC .RTM.- (1.7 .mu.m, 6.5 mM +
4.6 min, held DAD/SQD 2.1 .times. 50 mm) 5% CH.sub.3CN, for 0.4 min
B: CH.sub.3CN 2 Waters: Waters: A: 95% From 95% A 1 5 Acquity .RTM.
CSH .TM. C18 CH.sub.3COONH.sub.4 to 5% A in 50 IClass (1.7 .mu.m,
6.5 mM + 4.6 min, held UPLC .RTM.- 2.1 .times. 50 mm) 5%
CH.sub.3CN, for 0.4 min DAD/Xevo B: CH.sub.3CN G2-S QTOF 3 Agilent:
Waters: A: HCO.sub.3NH.sub.4 From 90% A 1.2 9 HP1100- XbridgeTM 10
mM + to 0% A in RT DAD, MSD C18 NH.sub.4OH 6.0 min, held G1956B
(5.0 .mu.m, (pH = 9.0) for 0.5 min, 4.6 .times. 100 mm) B:
CH.sub.3CN back to 90% A in 0.5 min, held for 2.0 min 4 Waters:
Waters: A: 95% From 95% A 1 5 Acquity .RTM. CSH .TM. C18
CH.sub.3COONH.sub.4 to 5% A in 50 IClass (1.7 .mu.m, 6.5 mM + 4.6
min, held UPLC .RTM.- 2.1 .times. 50 mm) 5% CH.sub.3CN, for 0.4 min
DAD/SQD B: CH.sub.3CN (*) Different MS tuning parameters due to low
sensitivity
TABLE-US-00021 TABLE 3 Analytical data-melting point (M.p.) and
LCMS: [M + H].sup.+ means the protonated mass of the free base of
the compound, [M - H].sup.- means the deprotonated mass of the free
base of the compound or the type of adduct specified [M +
CH.sub.3COO].sup.-). R.sub.t means retention time (in min). For
some compounds, exact mass was determined. Co. LCMS No. M.p.
(.degree. C.) [M + H] R.sub.t Method 1 228.68 (A) 440 2.26 1 2 n.d.
402 2.31 1 3 n.d. 488.1208 (-0.5 mDa) 2.29 2 4 167.9 (B) 376 1.82 1
5 119.88 (A) 438.1540 (-0.1 mDa) 2.63 2 6 156.03 (A) 404 2.23 1 7
n.d. 416.1696 (-0.2 mDa) 2.3 2 8 n.d. 430 2.42 1 9 n.d. 532.0705
(-0.3 mDa) 2.35 2 10 219.19 (A) 386 2.08 1 11 276.61(A) 454.1606
(+0.3 mDa) 1.94 2 12 176.92 (A) 362 1.78 1 13 n.d. 406 1.91 1 14
244.74 (A) 453.1653 (+0.3 mDa) 2.24 2 15 205.00 (A) 391 5.02 3 16
215.62 (A) 468.1758 (-0.mDa) 2.04 2 17 198.73 (A) 453.1653 (+0.3
mDa) 2.53 2 18 278.31 (A) 439.084 (-0.1 mDa) 2.55 2 19 n.d.
454.0957 (+0.7 mDa) 2.01 2 20 246.15 and 468.1764 (+0.5 mDa) 2.11 2
275.27 (A) 21 146.20 (A) 430.1856 (+0.2 mDa) 2.5 2 22 140.50 (A)
453.1651 (+0.1 mDa) 2.63 2 23 226.81 (A) 401 1.74 1 24 174.28 (A)
408.1447 (0.0 mDa) 1.97 2 25 n.d. 436 2.53 1 26 160.38 (A) 438 2.48
1 27 188.27 (A) 410.0993 (-0.2 mDa) 2.16 2 28 158.23 (A) 450.1309
(+0.1 mDa) 2.55 2 29 212.06 (A) 421 2.32 1 30 270.45 (A) 424.1151
(-0.1 mDa) 2.24 2 31 269.95 (A) 439 1.98 4 32 269.39 (A) 487.1274
(+1.3 mDa) 2.44 2 33 267.48 and 488.1216 (+0.3 mDa) 2.12 2 286.55
(A) 34 280.85 (A) 502 2.3 1 35 174.70 (A) 453.1063 (+1.0 mDa) 2.15
2 36 n.d. 467.1213 (+0.3 mDa) 2.31 2 37 131.60 and 473.111 (+0.6
mDa) 2.33 2 188.06 (A) 38 232.11 (A) 487.1267 (+0.6 mDa) 2.74 2 39
n.d. 473.1128 (+2.4 mDa) 2.67 2 40 n.d. 416.1698 (0.0 mDa) 2.36 2
41 n.d. 453.1661 (+1.1 mDa) 2.21 2 42 173.18 (A) 450.1308 (0.0 mDa)
2.63 2 43 227.75 (A) 474.1057 (0.0 mDa) 2.45 2 44 n.d. 440.1446
(0.0 mDa) 2.26 2 45 n.d. 513.1174 (+0.8 mDa) 2.40 2 n.d. means not
determined.
Optical Rotations
Optical rotations were measured on a Perkin-Elmer 341 polarimeter
with a sodium lamp and reported as follows: [.alpha.].sup.o
(.lamda., c g/100 ml, solvent, T .degree. C.).
[.alpha.].sub..lamda..sup.T=(100.alpha.)/(l.times.c): where l is
the path length in dm and c is the concentration in g/100 ml for a
sample at a temperature T (.degree. C.) and a wavelength .lamda.
(in nm). If the wavelength of light used is 589 nm (the sodium D
line), then the symbol D might be used instead. The sign of the
rotation (+ or -) should always be given. When using this equation
the concentration and solvent are always provided in parentheses
after the rotation. The rotation is reported using degrees and no
units of concentration are given (it is assumed to be g/100
mL).
TABLE-US-00022 TABLE 4 Optical Rotation data. Co. .alpha..sub.D
Wavelength Concentration Temp. No. (.degree.) (nm) w/v % Solvent
(.degree. C.) 1 +28.0 589 0.53 DMF 25 2 +25.7 589 0.59 DMF 20 4
+26.7 589 0.52 DMF 20 5 +19.5 589 0.73 DMF 20 6 +20.6 589 0.56 DMF
20 7 +18.9 589 0.51 DMF 20 10 +24.7 589 0.5 DMF 20 11 +20.7 589
0.54 DMF 20 12 +24.3 589 0.55 DMF 20 13 +21.8 589 0.57 DMF 20 14
+10.8 589 0.51 DMF 20 15 +21.9 589 0.5 DMF 20 16 -0.1 589 0.5 DMF
20 17 +0.4 589 0.5 DMF 20 18 +19.6 589 0.76 DMF 20 20 +16.1 589
0.51 DMF 20 21 +18.4 589 0.51 DMF 20 22 +9.6 589 0.5 DMF 20 23
+24.6 589 0.5 DMF 20 24 +24.3 589 0.53 DMF 20 25 +25.7 589 0.59 DMF
20 26 +26.1 589 0.57 DMF 20 27 +28.7 589 0.51 DMF 20 29 +29.9 589
0.46 DMF 20 30 +25.4 589 0.52 DMF 20 31 +27.3 589 0.55 DMF 20 32
+8.3 589 0.49 DMF 20 33 +26.6 589 0.48 DMF 20 34 +5.0 589 0.51 DMF
20 37 +19.6 589 0.76 DMF 20 38 +3.4 589 0.51 DMF 20 39 +14.7 589
0.5 DMF 20 40 +19.2 589 0.51 DMF 20 42 +25.0 589 0.53 DMF 20 43
+9.1 589 0.92 DMF 20 44 +1.0 589 0.30 DMF 20 45 n.d.* n.d.*: not
available data due to bad solubility
Pharmacological Examples
A) In Vitro Pharmacology
The compounds provided in the present invention are negative
allosteric modulators of mGluR2. These compounds appear to inhibit
glutamate responses by binding to an allosteric site other than the
glutamate binding site. The response of mGluR2 to a concentration
of glutamate is decreased when compounds of Formula (I) are
present. Compounds of Formula (I) are expected to have their effect
substantially at mGluR2 by virtue of their ability to reduce the
function of the receptor. The effects of negative allosteric
modulators tested at mGluR2 using the [.sup.35S]GTP.gamma.S binding
assay method described below and which is suitable for the
identification of such compounds, and more particularly the
compounds according to Formula (I), are shown in Table 7.
1) [.sup.35S]GTP.gamma.S Binding Assay
The [.sup.35S]GTP.gamma.S binding assay is a functional
membrane-based assay used to study G-protein coupled receptor
(GPCR) function whereby incorporation of a non-hydrolysable form of
GTP, [.sup.35S]GTP.gamma.S (guanosine 5'-triphosphate, labelled
with gamma-emitting .sup.35S), is measured. The G-protein a subunit
catalyzes the exchange of guanosine 5'-diphosphate (GDP) by
guanosine triphosphate (GTP) and on activation of the GPCR by an
agonist, [.sup.35S]GTP.gamma.S, becomes incorporated and cannot be
cleaved to continue the exchange cycle (Harper (1998) Current
Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.).
The amount of radioactive [.sup.35S]GTP.gamma.S incorporation is a
direct measure of the activity of the G-protein and hence the
activity of the antagonist can be determined. mGlu2 receptors are
shown to be preferentially coupled to G.alpha.i-protein, a
preferential coupling for this method, and hence it is widely used
to study receptor activation of mGlu2 receptors both in recombinant
cell lines and in tissues. Here we describe the use of the
[.sup.35S]GTP.gamma.S binding assay using membranes from cells
transfected with the human mGlu2 receptor and adapted from
Schaffhauser et al. (Molecular Pharmacology, 2003, 4:798-810) for
the detection of the negative allosteric modulation (NAM)
properties of the compounds of this invention.
Membrane Preparation
CHO-cells were cultured to pre-confluence and stimulated with 5 mM
butyrate for 24 h. Cells were then collected by scraping in PBS and
cell suspension was centrifuged (10 min at 4000 RPM in benchtop
centrifuge). Supernatant was discarded and pellet gently
resuspended in 50 mM Tris-HCl, pH 7.4 by mixing with an Ultra
Turrax homogenizer. The suspension was centrifuged at 12,400 RPM
(Sorvall F14S-6x250Y) for 10 minutes and the supernatant discarded.
The pellet was homogenized in 5 mM Tris-HCl, pH 7.4 using an Ultra
Turrax homogenizer and centrifuged again (13,000 RPM, 20 min,
4.degree. C.). The final pellet was resuspended in 50 mM Tris-HCl,
pH 7.4 and stored at -80.degree. C. in appropriate aliquots before
use. Protein concentration was determined by the Bradford method
(Bio-Rad, USA) with bovine serum albumin as standard.
[.sup.35S]GTP.gamma.S Binding Assay
Measurement of mGluR2 negative allosteric modulatory activity of
test compounds was performed as follows. Test compounds and
glutamate were diluted in assay buffer containing 10 mM HEPES acid,
10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl.sub.2 and 10 .mu.M
GDP. Human mGlu2 receptor-containing membranes were thawed on ice
and diluted in assay buffer supplemented with 18 .mu.g/ml saponin.
Membranes were pre-incubated with compound together with a
predefined (.about.EC.sub.80) concentration of glutamate (60 .mu.M)
for 30 min at 30.degree. C. After addition of [.sup.35S]GTP.gamma.S
(f.c. 0.1 nM), assay mixtures were shaken briefly and further
incubated to allow [.sup.35S]GTP.gamma.S incorporation on
activation (30 minutes, 30.degree. C.). Final assay mixtures
contained 7 .mu.g of membrane protein in 10 mM HEPES acid, 10 mM
HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl.sub.2, 10 .mu.M GDP and
10 .mu.g/ml saponin. Total reaction volume was 200 .mu.l. Reactions
were terminated by rapid filtration through Unifilter-96 GF/B
plates (Perkin Elmer, Massachusetts, USA) using a 96-well
filtermate universal harvester. Filters were washed 6 times with
ice-cold 10 mM NaH.sub.2PO.sub.4/10 mM Na.sub.2HPO.sub.4, pH 7.4.
Filters were then air-dried, and 30 .mu.l of liquid scintillation
cocktail (Microscint-O) was added to each well. Membrane-bound
radioactivity was counted in a Topcount.
Data Analysis
The concentration-response curves of representative compounds of
the present invention were generated using the Lexis software
interface (developed at J&J). Data were calculated as % of the
control glutamate response, defined as the response that is
generated upon addition of an EC.sub.80-equivalent concentration of
glutamate. Sigmoid concentration-response curves plotting these
percentages versus the log concentration of the test compound were
analyzed using non-linear regression analysis. The concentration
producing half-maximal inhibition was calculated as the
IC.sub.50.
The pIC.sub.50 values were calculated as the -log IC.sub.50, when
the IC.sub.50 is expressed in M. E.sub.max is defined as the
relative maximal effect (i.e. maximal % inhibition relative to the
control glutamate response).
TABLE-US-00023 TABLE 5 Pharmacological data for compounds according
to the invention. GTP.gamma.S- GTP.gamma.S- hmGluR2 hmGluR2 Co.
anGT anGT No. pIC.sub.50 Emax 1 7.94 99.26 2 7.7 103.485 3 7.6
107.81 4 7.59 103.88 5 7.56 104.81 6 7.51 103.905 7 7.5 105.645 8
7.48 107.65 9 7.46 108.155 10 7.44 106.915 11 7.26 108.945 12 7.15
100.61 13 7.08 103.715 14 6.96 102.565 15 6.77 102.105 16 6.73
108.14 17 6.84 106.335 18 8.04 110.345 19 7.3 107.82 20 7.27
107.245 21 8.24 107.93 22 7.79 109.72 23 7.19 103.86 24 7.8 106.205
25 8.7 105.86 26 8.57 111.21 27 8.46 106.485 28 8.43 111.495 29
8.41 111.36 30 8.2 108.795 31 7.99 107.24 32 7.81 108.8 33 7.79
106.065 34 7.51 108.665 35 7.42 110.71 36 6.96 106.185 37 7.89
109.01 38 7.67 105.425 39 8.08 103.79 40 8.16 107.01 41 6.78
105.555 42 8.73 109.175 43 8.31 105.635 44 7.41 103.425 45 7.46
105.79
B) In Vivo Pharmacology 1) Reversal of LY-404039-induced Decrease
of Palpebral Opening in Apomorphine-challenged Rats.
Male Wiga Wistar rats (Crl:WI; Charles River Germany; 220.+-.40 g)
were housed under standard laboratory conditions (21.+-.2.degree.
C.; 50-65% relative humidity; light-dark cycle set at 12 h; lights
on at 6.00 h) and fasted overnight prior to the start of the
experiments (tap water remained available ad libitum). During the
test period, they were housed in individual cages. Palpebral
opening was scored every 5 min over the first hour after injection
of apomorphine (1.0 mg/kg, i.v.) in animals either pretreated or
not pretreated with LY-404039 (2.5 mg/kg, s.c.) at 1 h prior to the
apomorphine injection. The animals were also pretreated with test
compound or solvent at a predefined interval before apomorphine
challenge. The score system was: (5) exophthalmos, (4) wide open,
(3) open for three-quarters, (2) half open, (1) open for
one-quarter, (0) closed. The scores for palpebral opening were
cumulated over the 60-min observation period. A cumulative
palpebral opening score>26 was selected for drug-induced
reversal of the LY-404039-induced decrease of palpebral opening
(occurrence in 3.2% of control animals pretreated with LY-404039
(n=154) versus in 99.5% of control rats not pretreated with
LY-404039 (n=6335)).
Table 6 shows the palpebral opening score in control animals
receiving apomorphine alone and in animals receiving apomorphine
and LY-404039. In animals receiving apomorphine alone the median
palpebral opening is 43 whereas in animals receiving apomorphine
and LY-404039, the median palpebral opening is 17. In animals
treated with apomorphine alone, the palpebral opening score is
almost always (in 95.5% of the rats) greater than 34, whereas in
animals treated with the combination (apomorphine+LY-404039) only
3.2% of the animals show a palpebral opening greater than 26.
TABLE-US-00024 TABLE 6 Palpebral opening score in control animals.
Apomorphine Apomorphine + alone LY-404039 Measurement (n = 6335) (n
= 154) Palpebral opening score Median score: 43 17 Occurrence score
> 26 (%): 99.5 3.2 Occurrence score > 34 (%): 95.9 0.0
2) Reversal of the Effect of the mGluR2 PAM JNJ-42153605-induced
Inhibition of Scopolamine-induced Hyperlocomotion Apparatus
Motor activity was measured in microprocessor-based motor activity
arenas (closed gray PVC cylinders with a height of 39 cm and a
diameter of 31 cm). Each arena was placed on an infrared LED
(8.times.8 LEDs) lit box (white PVC squared box; 40.times.40
cm.sup.2; height 12.5 cm. An infrared-sensitive tube camera and a
white light source were mounted to the ceiling above the
observation chamber to track the animal. The total distance
traveled (cm) was recorded and analyzed using the Noldus Ethovision
XT Video Tracking System (Version 7.0.418; Noldus, Wageningen, The
Netherlands). The intensity of the light within the activity cages
(measured in the centre at the level of the floor) ranged between 4
and 8 LUX.
General Procedure
The rats were pretreated with test compound or vehicle at 60 min
before the start of the activity recordings and placed into
individual cages. The rats were challenged with JNJ-42153605
(3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,-
2,4]triazolo[4,3-a]pyridine; WO2010/130424; Cid et al. J. Med.
Chem. 2012, 55, 8770-8789) (20 mg/kg, i.v.) 30 min before the start
of the activity recording combined with scopolamine (0.16 mg/kg,
i.v.) just before the start of the activity measurements.
Immediately after the injection of scopolamine, the rats were
placed into the activity monitors and total distance traveled over
the first 30 min was measured.
Solvent-pretreated Control Rats.
Frequency distributions obtained in a historical series of
solvent-pretreated control rats are given in Table 7 below. Animals
receiving the combination of JNJ-42153605 and scopolamine (n=433)
almost always traveled a distance of less than 1500 cm (<1500
cm) (only 2.5% of the control rats traveled a distance of more than
1500 cm (>1500 cm)). On the other hand, animals challenged with
scopolamine alone (n=215) always traveled a total distance of more
than 1500 cm (>1500 cm) and almost always (in 95.8% of the rats)
a distance of more than 4400 cm (>4400 cm). Rats that did not
receive any challenge traveled almost always a distance of more
than 1500 cm (>1500 cm) (in 93.3% of the rats) and less than
4400 cm (<4400 cm) (in 98.9% of the rats). For reversal of the
inhibitory effect of JNJ-42153605 on the scopolamine-induced
hyperlocomotion, the following all-or-none criteria were adopted:
(1) reversal: total distance>1500 cm.
TABLE-US-00025 TABLE 7 Frequency distributions obtained in
historical series of solvent-pretreated control rats. N.sub.tested
means number of animals tested. Median >1500 cm >4400 cm (cm)
(%) (%) N.sub.tested Combination 480 2.5 0.0 433 No challenge 2618
93.3 1.1 638 Scopolamine 7246 100 95.8 215
3) Induction of Mydriasis
The pupil diameter of Wiga rats was measured with a microscopic
micrometer (1 unit= 1/24 mm). Criteria for drug-induced effects:
pupil diameter>25 units for mydriasis (in controls: 1.9%) 1 h
post-administration of the test compound (test 1) or 1, 2 or 3 h
post-administration of the test compound (test 2, wherein the
maximum pupil diameter over the full 3 h period is reported).
Table 8 below provides the data obtained in the tests 1)-3)
described above:
TABLE-US-00026 TABLE 8 Summary of data in tests 1)-3). In the
table: SCOP JNJ-42153605 means Reversal of the effect of JNJ
42153605 on scopolamine-induced hyperlocomotion, APO LY-404039
means Reversal of LY-404039-induced decrease of palpebral opening
in apomorphine challenged rats, MYD means Induction of mydriasis,
ED.sub.50 means median effective dose; PO means oral route.
ED.sub.50 (mg/kg) Co. SCOP APO MYD No. Route JNJ-42153605 LY-404039
Test 1 Test 2 4 PO >2.5 27 PO >2.5 (*) 0.2 >10 >40 25
PO 0.726 0.79 26 PO 1.99 29 PO >2.5 31 PO >0.63 30 PO 1.99 28
PO >0.63 32 PO >0.63 11 PO >0.63 7 PO >0.63 16 PO
>0.63 34 PO >0.63 33 PO >0.63 22 PO >0.63 21 PO
>0.63 18 PO >0.63 (*) ED.sub.50 = 1.25 mg/kg when applying a
more sensitive criterion for drug-induced reversal of total
distance >1300 cm (occurring in only 4.8% of solvent-pretreated
rats)
Prophetic Composition Examples
"Active ingredient" as used throughout these examples relates to a
final compound of Formula (I), the pharmaceutically acceptable
salts thereof, the solvates and the stereochemically isomeric forms
and the tautomers thereof.
Typical examples of recipes for the formulation of the invention
are as follows:
1. Tablets
TABLE-US-00027 Active ingredient 5 to 50 mg Di-calcium phosphate 20
mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch
ad 200 mg
In this Example, active ingredient can be replaced with the same
amount of any of the compounds according to the present invention,
in particular by the same amount of any of the exemplified
compounds.
2. Suspension
An aqueous suspension is prepared for oral administration so that
each 1 milliliter contains 1 to 5 mg of one of the active
compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium
benzoate, 500 mg of sorbitol and water ad 1 ml.
3. Injectable
A parenteral composition is prepared by stirring 1.5% by weight of
active ingredient of the invention in 10% by volume propylene
glycol in water.
4. Ointment
TABLE-US-00028 Active ingredient 5 to 1000 mg Stearyl alcohol 3 g
Lanoline 5 g White petroleum 15 g Water ad 100 g
In this Example, active ingredient can be replaced with the same
amount of any of the compounds according to the present invention,
in particular by the same amount of any of the exemplified
compounds.
Reasonable variations are not to be regarded as a departure from
the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
* * * * *
References